The DOI matches its Crossref record, with a small difference in title or year; 127 of the 127 references it cites were found in a registry or an index; 43 of the 164 sources its claims cite were checked for support.
Cytokines and Glucocorticoid Receptor Signaling
Open accessAbstract
Data suggest that the activation of immune responses and the release of inflammatory cytokines may play a role in the pathophysiology of major depression. One mechanism by which cytokines may contribute to depression is through their effects on the glucocorticoid receptor (GR). Altered GR function in depression has been demonstrated by neuroendocrine challenge tests that reliably reveal reduced GR sensitivity as manifested by nonsuppression of cortisol following dexamethasone administration in vivo and lack of immune suppression following administration of glucocorticoids in vitro. Relevant to the GR, cytokines have been shown to decrease GR expression, block translocation of the GR from cytoplasm to nucleus, and disrupt GR‐DNA binding through nuclear protein‐protein interactions. In addition, cytokines have been shown to increase the expression of the relatively inert GR beta isoform. Specific cytokine signaling molecules that have been shown to be involved in the disruption of GR activity include p38 mitogen‐activated protein kinase, which is associated with reduced GR translocation, and signal transducer and activator of transcription (STAT)5, which binds to GR in the nucleus. Nuclear factor‐κB (NF‐κB) also has been shown to lead to GR suppression through mutually inhibitory GR‐NF‐κB nuclear interactions. Interestingly, several antidepressants have been shown to enhance GR function, as has activation of protein kinase A (PKA). Antidepressants and PKA activation have also been found to inhibit inflammatory cytokines and their signaling pathways, suggesting that drugs that target both inflammatory responses and the GR may have special efficacy in the treatment of depression.
Overview
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Written from the paper’s full text.
TL;DR
This review proposes that innate immune cytokines contribute to glucocorticoid resistance in major depression by disrupting glucocorticoid receptor (GR) signaling at multiple levels, including GR translocation, DNA binding, and isoform expression. It further suggests that treatments enhancing GR function while inhibiting inflammatory pathways may have special efficacy in depression.
Key findings
- Cytokines reduce GR function through p38 MAPK, JNK, ERK, Jak-STAT5, and NF-κB signaling, affecting GR translocation, GR-DNA binding, protein-protein interactions, and GR isoform expression. In HeLaS3 and CEMC7 cells, TNF-α or IL-1 increased hGR-β expression two-fold while increasing hGR-α only 1.5-fold.
- Major depression is associated with both increased inflammatory markers and glucocorticoid resistance; DEX nonsuppression rates in depressed patients range from 25% to 80% depending on age, sex, severity, and test type, with the DEX-CRF test believed more sensitive than the DST.
- In an IFN-α model, 45% of patients receiving high-dose IFN-α for cancer met criteria for major depression, and one third dropped out due to behavioral toxicity; 12 weeks of IFN-α plus ribavirin flattened the cortisol curve, which correlated with depressive symptoms and fatigue.
- Chronic caregiving stress was associated with increased monocyte expression of NF-κB promoter-containing genes and decreased GR promoter-containing genes, increased IL-1ra and CRP (mean >3 mg/L, high-risk category), with no group difference in salivary cortisol over 3 consecutive days.
Methods
- Narrative review synthesizing published in vitro, animal, and human studies on cytokine effects on GR signaling and their relevance to major depression.
- Evidence reviewed includes cell lines (e.g., mouse L929 fibroblasts, rat PC12 cells, human cells), animal stress models, and human studies of depression, IFN-α treatment, and chronic caregiving stress.
- Main analysis is qualitative synthesis of cited literature, including mechanistic pathways and treatment implications; no primary experimental cohort or systematic search is described.
Limitations
- Stated: a role for hGR-β in major depression has yet to be established; whether the reciprocal inflammatory-GR relationship occurs in depression remains to be established; future studies are needed to examine the relative balance of glucocorticoid and innate immune signaling and therapeutic strategies.
- Stated: cross-sectional studies of inflammation and glucocorticoid resistance in major depression have yielded mixed results.
- Evident: as a narrative review, it lacks a systematic search or meta-analysis, and causal direction in human depression is not established; many mechanistic findings derive from cell lines or animal models.
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Claims the paper makes
90 No full text of the sources · 19 No basis given · 15 Supported · 15 Partly supported · 15 Own interpretation · 6 Couldn’t confirm · 3 Supported so far · 3 Not checked yet · 1 Sources not found · accuracy not yet measured
Every source the paper cites for this claim was checked and supports it.
In the paper
“Mounting data indicate that insufficient glucocorticoid signaling in major depression and potentially other clinical disorders may be a consequence of the impact of innate immune cytokines on the receptors for glucocorticoid hormones.11”
§ Cytokines and Glucocorticoid Receptor Signaling > Introduction
What the sources say
- Supportedcites [11] Pace TW Hu F Miller A 2007 Cytokine-effects on glucocorticoid receptor function: relevance to glucocorticoid resistance and the pathophysiology and treatment of major depression Brain Behav Immun 21 9 19 17070667 PMC1820632 source
The Introduction identifies major depression and other disorders as associated with glucocorticoid resistance, and says proinflammatory cytokines may impair glucocorticoid receptor function in depression. The Summary and Conclusions says cytokine signaling can suppress receptor signaling and thereby contribute to glucocorticoid resistance. (LLM, conf=0.92)
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“These effects of innate immune cytokines on glucocorticoid receptors (GRs) may represent a contributing pathophysiologic pathway to the development of major depression”
§ Cytokines and Glucocorticoid Receptor Signaling > Introduction
What the sources say
- Supportedcites [11] Pace TW Hu F Miller A 2007 Cytokine-effects on glucocorticoid receptor function: relevance to glucocorticoid resistance and the pathophysiology and treatment of major depression Brain Behav Immun 21 9 19 17070667 PMC1820632 source
The Introduction says cytokines may alter GR function in major depression and links their effects on GR signaling to glucocorticoid resistance. The Summary and Conclusions further describes disrupted GR signaling as a potential contributor to behavioral alterations and the development of psychiatric diseases, including depression. This supports the claim’s qualified wording. (LLM, conf=0.92)
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“data indicate that cytokines can influence virtually every pathophysiologic pathway relevant to depression, including neurotransmitter metabolism, neuroendocrine function, synaptic plasticity and regional brain activity.”
§ Cytokines and Glucocorticoid Receptor Signaling > Inflammation and Major Depression
What the sources say
- Partly supportedcites [16] Dantzer R 2008 From inflammation to sickness and depression: when the immune system subjugates the brain Nat Rev Neurosci 9 46 56 18073775 PMC2919277 sourceExperimental — accuracy not yet measured
The review’s discussion of alternative mechanisms describes effects on serotonin metabolism and neurotransmission, and its neuroendocrine discussion describes cytokine activation of the hypothalamus–pituitary–adrenal axis. Its neuroanatomy discussion reports altered activity in particular brain regions. The copy does not establish effects on synaptic plasticity as a depression pathway or support the broader assertion that cytokines influence virtually every relevant pathway; long-term potentiation appears only in a reference title. Page numbers are unavailable in the indexed copy. (LLM, conf=0.86)
hedgeddirect- Asserted: passes — The authors put it forward as true.
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- Partly supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“cytokine-induced activation of the enzyme, indolamine 2,3 dioxygenase (IDO), which metabolizes tryptophan to kynurenine and quinolinic acid, is believed to contribute to reduced availability of serotonin.16,23,24”
§ Cytokines and Glucocorticoid Receptor Signaling > Inflammation and Major Depression
What the sources say
- Supportedcites [16] Dantzer R 2008 From inflammation to sickness and depression: when the immune system subjugates the brain Nat Rev Neurosci 9 46 56 18073775 PMC2919277 source
Box 1 says pro-inflammatory cytokines induce IDO, which degrades tryptophan through the kynurenine pathway; kynurenine can then be metabolized to quinolinic acid. The same passage says reduced tryptophan can affect serotonin synthesis, supporting the claim’s qualified wording about reduced serotonin availability. The copy provides no page numbers for these passages. (LLM, conf=0.90)
- Not checked — no full text of the sourcecites [23] Muller N Schwarz M 2007 The immune-mediated alteration of serotonin and glutamate: towards an integrated view of depression Mol Psychiatry 12 988 1000 17457312 source
- Not checked — no full text of the sourcecites [24] Wichers M 2005 IDO and interferon-alpha-induced depressive symptoms: a shift in hypothesis from tryptophan depletion to neurotoxicity Mol Psychiatry 10 538 544 15494706 source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“data from laboratory animals and humans indicate that the administration of innate immune cytokines, including interferon (IFN)-α, leads to multiple behavioral changes that overlap with major depression, including depressed mood, anhedonia, fatigue, psychomotor slowing, disrupted sleep, cognitive impairment, anxiety, and suicidal ideation.6,16”
§ Cytokines and Glucocorticoid Receptor Signaling > Inflammation and Major Depression
What the sources say
- Not checked — no full text of the sourcecites [6] Raison C Capuron L Miller A 2006 Cytokines sing the blues: inflammation and the pathogenesis of depression Trends Immunol 27 24 31 16316783 PMC3392963 source
- Partly supportedcites [16] Dantzer R 2008 From inflammation to sickness and depression: when the immune system subjugates the brain Nat Rev Neurosci 9 46 56 18073775 PMC2919277 sourceExperimental — accuracy not yet measured
The passage on immunotherapy symptoms (labelled Abstract; no page given) reports that IL-2 and IFN-α treatment causes fatigue, sleep disorders, mild cognitive changes and depressed mood, sometimes with anxiety. The paper also discusses anhedonia in cytokine-induced sickness behaviour. It does not report suicidal ideation, and its discussion of psychomotor retardation describes clinical depression rather than clearly identifying it as an effect of cytokine administration. (LLM, conf=0.86)
hedgeddirect- Asserted: passes — The authors put it forward as true.
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The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“both JNK and p38 signaling pathways have been implicated in the inhibitory effects of TNF-α on GR function.47”
§ Cytokines and Glucocorticoid Receptor Signaling > Cytokine Effects on GR Function
What the sources say
- Could not verifycites [47] Xu Q 2004 CD56+ cells induce steroid resistance in B cells exposed to IL-15 J Immunol 172 7110 7115 15153534 sourceExperimental — accuracy not yet measured
The Discussion describes glucocorticoid receptor nuclear translocation and steroid resistance associated with IL-15/IL-4, but does not link TNF-α to impaired receptor function through JNK or p38. Searches for the claimed pathways and TNF-α–receptor mechanism found no passage addressing that relationship in our copy. (LLM, conf=0.74)
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Could not verify
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“an equivalent of hGR-β has yet to be described in other species, including mice and rats.77,78”
§ Cytokines and Glucocorticoid Receptor Signaling > Cytokine Effects on GR Function
What the sources say
- Supportedcites [77] Otto C Reichardt H Schutz G 1997 Absence of glucocorticoid receptor-beta in mice J Biol Chem 272 26665 26668 9334249 source
The introduction states that GRβ had been studied exclusively in human tissues. The Abstract reports no GRβ mRNA in the adult mouse tissues examined, and the Discussion describes a putative rat exon that differs substantially from human exon 9β. Together, these support the claim that a human GRβ equivalent had not been described in mice, rats, or other species. (LLM, conf=0.90)
- Not checked — no full text of the sourcecites [78] De Kloet E 1998 Brain corticosteroid receptor balance in health and disease Endocr Rev 19 269 301 9626555 source
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“reduced skin sensitivity to topical glucocorticoid administration in depressed patients was found to significantly correlate with increased blood concentrations of TNF-α.40”
§ Cytokines and Glucocorticoid Receptor Signaling > Relationship between Inflammation and GR Signaling in Major Depression and Stress
What the sources say
- Supportedcites [40] Fitzgerald P 2006 Cutaneous glucocorticoid receptor sensitivity and pro-inflammatory cytokine levels in antidepressant-resistant depression Psychol Med 36 37 43 16255837 source
The Correlations section reports a significant inverse correlation between circulating TNF-α and skin vasoconstriction scores in the depressed patients (r = −0.46, p = 0.04). The Discussion explains that a lower vasoconstriction score indicates less cutaneous glucocorticoid sensitivity. The patients studied had antidepressant-resistant depression. (LLM, conf=0.93)
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“ibuprofen and other nonsteroidal anti-inflammatory drugs have been shown to inhibit p38 MAPK activity in Jurkat T cells,72,73”
§ Cytokines and Glucocorticoid Receptor Signaling > Cytokine Effects on GR Function
What the sources say
- Supportedcites [72] Paccani S 2002 Nonsteroidal anti-inflammatory drugs suppress T-cell activation by inhibiting p38 MAPK induction J Biol Chem 277 1509 1513 11700329 source
The Results and Discussion report that TCR-induced p38 activity in Jurkat T cells was dramatically inhibited by nonselective and COX-1-selective NSAIDs. Figure 3A includes ibuprofen among the drugs tested. The finding concerns TCR-induced activity; the paper reports no effect from the COX-2 inhibitor NS-398. (LLM, conf=0.92)
- Supportedcites [73] Paccani S 2005 Nonsteroidal anti-inflammatory drugs inhibit a Fyn-dependent pathway coupled to Rac and stress kinase activation in TCR signaling Blood 105 2042 2048 15514010 source
The COX-1 is required for p38 and JNK stress kinase activation section reports that ibuprofen and the COX-1-selective NSAID sc-560 inhibited TCR-dependent p38 activation. Figure 1 identifies the tested cells as Jurkat T cells. The finding concerns p38 activation after TCR stimulation, not direct inhibition of the kinase. (LLM, conf=0.91)
boosteddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“There is a rich database demonstrating that cytokines can influence GR function at multiple levels, including GR translocation from cytoplasm to nucleus, GR protein-protein interactions, GR binding to its DNA response element, and induction of GR isoforms that have reduced capacity to bind ligand and access to hormone.11”
§ Cytokines and Glucocorticoid Receptor Signaling > Cytokine Effects on GR Function
What the sources say
- Supportedcites [11] Pace TW Hu F Miller A 2007 Cytokine-effects on glucocorticoid receptor function: relevance to glucocorticoid resistance and the pathophysiology and treatment of major depression Brain Behav Immun 21 9 19 17070667 PMC1820632 source
Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“inhibition of prednisolone-induced GR translocation, as well as GR-mediated gene transcription in human epidermal cells by TNF-α, is dependent on ERK activation.46”
§ Cytokines and Glucocorticoid Receptor Signaling > Cytokine Effects on GR Function
What the sources say
- Could not verifycites [46] Goleva E Kisich K Leung D 2002 A role for STAT5 in the pathogenesis of IL-2-induced glucocorticoid resistance J Immunol 169 5934 5940 12421978 sourceExperimental — accuracy not yet measured
The Discussion and the section on JAK3 inhibition describe IL-2-induced glucocorticoid resistance in T cells, involving STAT5, JAK3 and p38 MAPK. Searches for TNF-α, ERK, prednisolone and human epidermal cells found no passage addressing the claimed mechanism; the paper’s findings do not establish or contradict it. (LLM, conf=0.76)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Could not verify
Every source the paper cites for this claim was checked and supports it.
In the paper
“activation of JNK has also been shown to result in increased nuclear export of GR.63”
§ Cytokines and Glucocorticoid Receptor Signaling > Cytokine Effects on GR Function
What the sources say
- Supportedcites [63] Itoh M 2002 Nuclear export of glucocorticoid receptor is enhanced by c-Jun N-terminal kinase-mediated phosphorylation Mol Endocrinol 16 2382 2392 12351702 source
The Discussion states that JNK activation strongly enhances GR nuclear export within 1–2 hours and reports enhanced export after UV irradiation or JNK1 overexpression. This directly supports the citing sentence. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“Changes in nuclear translocation of GR were not associated with JNK inhibition.”
§ Cytokines and Glucocorticoid Receptor Signaling > Cytokine Effects on GR Function
What the sources say
- Could not verifycites [48] Biola A 2001 Interleukin-2 inhibits glucocorticoid receptor transcriptional activity through a mechanism involving STAT5 (signal transducer and activator of transcription 5) but not AP-1 Mol Endocrinol 15 1062 1076 11435608 sourceExperimental — accuracy not yet measured
The discussion passage on IL-2 and GR signaling says IL-2 did not prevent GR translocation to the nucleus, but it does not assess changes in translocation in relation to JNK inhibition. Searches for “JNK” and “c-Jun N-terminal kinase” found no passage addressing that relationship. (LLM, conf=0.73)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Could not verify
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Reduced sensitivity to glucocorticoids in depressed patients is also evident in immune cells stimulated in vitro and in the skin following topical application of glucocorticoids.7,11,40”
§ Cytokines and Glucocorticoid Receptor Signaling > Glucocorticoid Resistance in Major Depression
What the sources say
- Not checked — no full text of the sourcecites [7] Pariante C Miller A 2001 Glucocorticoid receptors in major depression: relevance to pathophysiology and treatment Biol Psychiatry 49 391 404 11274650 source
- Partly supportedcites [11] Pace TW Hu F Miller A 2007 Cytokine-effects on glucocorticoid receptor function: relevance to glucocorticoid resistance and the pathophysiology and treatment of major depression Brain Behav Immun 21 9 19 17070667 PMC1820632 sourceExperimental — accuracy not yet measured
The Introduction reports reduced glucocorticoid inhibition of immune-cell responses after in vitro exposure in depressed patients, compared with healthy controls. It does not report reduced skin sensitivity following topical glucocorticoid application; a search for topical application found no supporting passage in our copy. Page numbers were not available. (LLM, conf=0.87)
- Partly supportedcites [40] Fitzgerald P 2006 Cutaneous glucocorticoid receptor sensitivity and pro-inflammatory cytokine levels in antidepressant-resistant depression Psychol Med 36 37 43 16255837 sourceExperimental — accuracy not yet measured
The Discussion reports reduced skin-blanching after topical steroid application in antidepressant-resistant depressed patients compared with healthy controls. The paper does not report reduced glucocorticoid sensitivity in immune cells stimulated in vitro; its blood assays measured circulating cytokines. That part of the claim is not supported by this source. (LLM, conf=0.86)
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“These latter findings indicate that decreased glucocorticoid responsiveness in depressed patients is not solely a function of altered in vivo pharmacokinetic properties of glucocorticoids (including DEX) in depressed patients.”
§ Cytokines and Glucocorticoid Receptor Signaling > Glucocorticoid Resistance in Major Depression
What the sources say
- Not checked — no full text of the sourcecites [7] Pariante C Miller A 2001 Glucocorticoid receptors in major depression: relevance to pathophysiology and treatment Biol Psychiatry 49 391 404 11274650 source
- Supportedcites [11] Pace TW Hu F Miller A 2007 Cytokine-effects on glucocorticoid receptor function: relevance to glucocorticoid resistance and the pathophysiology and treatment of major depression Brain Behav Immun 21 9 19 17070667 PMC1820632 source
The Introduction states that evidence from both in vivo and in vitro measures shows glucocorticoid resistance in depressed individuals is not solely a function of dexamethasone bioavailability in vivo. It also describes reduced responses to dexamethasone in immune cells exposed in vitro, supporting the distinction from altered in vivo drug availability. (LLM, conf=0.94)
- Partly supportedcites [40] Fitzgerald P 2006 Cutaneous glucocorticoid receptor sensitivity and pro-inflammatory cytokine levels in antidepressant-resistant depression Psychol Med 36 37 43 16255837 sourceExperimental — accuracy not yet measured
The Results (SIV) report reduced skin blanching after topical steroids in antidepressant-resistant depressed patients, supporting reduced responsiveness in a setting that does not depend on systemic delivery. But the paper does not test glucocorticoid pharmacokinetics or dexamethasone specifically, and the Discussion limits its conclusion to cutaneous responsiveness rather than depressed patients generally. (LLM, conf=0.84)
hedged- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“Comparable effects were observed after treatment of cells with antisense oligonucleotides directed against JNK.”
§ Cytokines and Glucocorticoid Receptor Signaling > Cytokine Effects on GR Function
What the sources say
- Could not verifycites [48] Biola A 2001 Interleukin-2 inhibits glucocorticoid receptor transcriptional activity through a mechanism involving STAT5 (signal transducer and activator of transcription 5) but not AP-1 Mol Endocrinol 15 1062 1076 11435608 sourceExperimental — accuracy not yet measured
The EMSA and DNA Affinity Precipitation methods describe oligonucleotide probes and IL-2 treatment, but not antisense oligonucleotides directed against JNK. Searches for JNK, antisense oligonucleotides, and comparable treatment effects found no passage in our copy addressing the claim. (LLM, conf=0.76)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Could not verify
Every source the paper cites for this claim was checked and supports it.
In the paper
“Inhibition of GR function by activation of ERK is believed to be in part related to phosphorylation of GR cofactors.65”
§ Cytokines and Glucocorticoid Receptor Signaling > Cytokine Effects on GR Function
What the sources say
- Supportedcites [65] Rogatsky I Logan S Garabedian M 1998 Antagonism of glucocorticoid receptor transcriptional activation by the c-Jun N-terminal kinase Proc Natl Acad Sci USA 95 2050 2055 9482836 PMC19245 source
The Results report that ERK activation reduces GR-dependent transcriptional activity. The Discussion proposes that this suppression may reflect modification of a GR cofactor by ERK, matching the citing sentence’s qualified account of the mechanism. Page numbers are not supplied in our copy. (LLM, conf=0.92)
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“Recent data also indicate that anisomycin is a potent activator of JNK signaling pathways,73”
§ Cytokines and Glucocorticoid Receptor Signaling > Cytokine Effects on GR Function
What the sources say
- Could not verifycites [73] Paccani S 2005 Nonsteroidal anti-inflammatory drugs inhibit a Fyn-dependent pathway coupled to Rac and stress kinase activation in TCR signaling Blood 105 2042 2048 15514010 sourceExperimental — accuracy not yet measured
The section “COX-1 is required for p38 and JNK stress kinase activation” discusses JNK activation following TCR engagement, but does not address anisomycin. Searches for “anisomycin” and the claim’s phrasing found no passage about its effect on JNK; page numbers were not available in our copy. (LLM, conf=0.76)
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Could not verify
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In the paper
“taken together, these data indicate that reduced glucocorticoid signaling is apparent in a number of cell types and tissues, including neuroendocrine, immune and dermal elements.”
§ Cytokines and Glucocorticoid Receptor Signaling > Glucocorticoid Resistance in Major Depression
What the sources say
- Not checked — no full text of the sourcecites [7] Pariante C Miller A 2001 Glucocorticoid receptors in major depression: relevance to pathophysiology and treatment Biol Psychiatry 49 391 404 11274650 source
- Partly supportedcites [11] Pace TW Hu F Miller A 2007 Cytokine-effects on glucocorticoid receptor function: relevance to glucocorticoid resistance and the pathophysiology and treatment of major depression Brain Behav Immun 21 9 19 17070667 PMC1820632 sourceExperimental — accuracy not yet measured
The Introduction (page not available) says impaired glucocorticoid sensitivity is widespread in neuroendocrine and immune tissues. It does not identify dermal tissues or cells as another site of reduced signaling, so the dermal part of the claim is unsupported. (LLM, conf=0.86)
- Partly supportedcites [40] Fitzgerald P 2006 Cutaneous glucocorticoid receptor sensitivity and pro-inflammatory cytokine levels in antidepressant-resistant depression Psychol Med 36 37 43 16255837 sourceExperimental — accuracy not yet measured
The Introduction (page not provided) discusses possible reduced glucocorticoid-receptor sensitivity in the HPA axis and abnormalities in peripheral blood cells; the Discussion reports reduced cutaneous sensitivity in antidepressant-resistant depression. But the Discussion cautions that cutaneous subsensitivity does not necessarily extend to other tissues, so the claim presents reduced signaling across cell types more definitively than the paper does. (LLM, conf=0.86)
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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- Based: passes — The paper gives a reason why it holds.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Studies in our lab have shown that JNK may play an important role in GR regulation under resting (unstimulated) conditions through mutually inhibitory protein-protein interactions.48”
§ Cytokines and Glucocorticoid Receptor Signaling > Cytokine Effects on GR Function
What the sources say
- Partly supportedcites [48] Biola A 2001 Interleukin-2 inhibits glucocorticoid receptor transcriptional activity through a mechanism involving STAT5 (signal transducer and activator of transcription 5) but not AP-1 Mol Endocrinol 15 1062 1076 11435608 sourceExperimental — accuracy not yet measured
The Introduction says GR can interact with other transcription factors, and the discussion describes mutual interference between GR and AP-1. Neither passage identifies JNK as the interacting factor or establishes GR regulation by JNK under resting conditions; the paper's own inhibitory mechanism involves IL-2 and STAT5. (LLM, conf=0.78)
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
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In the paper
“treatment of HeLaS3 and CEMC7 cells with either TNF-α or IL-1 was shown to increase hGR β expression two-fold, while only increasing hGR-α 1.5-fold.75”
§ Cytokines and Glucocorticoid Receptor Signaling > Cytokine Effects on GR Function
What the sources say
- Partly supportedcites [75] Webster J 2001 Proinflammatory cytokines regulate human glucocorticoid receptor gene expression and lead to the accumulation of the dominant negative beta isoform: a mechanism for the generation of glucocorticoid resistance PNAS 98 6865 6870 11381138 PMC34444 sourceExperimental — accuracy not yet measured
The Results (Figs. 3–4; page unavailable in our copy) support a roughly 1.5-fold increase in GRα and a larger increase in GRβ after cytokine treatment of these cells. They do not support the claimed two-fold GRβ increase across both cells and both treatments: the reported protein increases are 3.5-fold for TNF-α-treated HeLaS3 cells, 4.0-fold for TNF-α-treated CEMC7 cells, and 4.0–5.5-fold after IL-1 treatment. (LLM, conf=0.90)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
- Partly supported
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In the paper
“cAMP has been found to inhibit IL-6–induced DNA binding of STAT1 and STAT3.116”
§ Cytokines and Glucocorticoid Receptor Signaling > Treatment Implications > PKA
What the sources say
- Partly supportedcites [116] Sengupta T Schmitt E Ivashkiv L 1996 Inhibition of cytokines and JAK-STAT activation by distinct signaling pathways Proc Natl Acad Sci USA 93 9499 9504 8790359 PMC38457 sourceExperimental — accuracy not yet measured
The Abstract reports inhibition of IL-6-induced STAT3 DNA binding in the context of cAMP-mediated interruption of JAK–STAT signaling. It describes STAT1 inhibition in response to interferon gamma, not IL-6, so the STAT1 portion of the claim is not supported. (LLM, conf=0.84)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Other antidepressants, including clomipramine, fluoxetine, paroxetine, and citalopram, are also known to exert these effects on GR.103”
§ Cytokines and Glucocorticoid Receptor Signaling > Treatment Implications > Antidepressants
What the sources say
- Partly supportedcites [103] Pariante C 2001 Antidepressants enhance glucocorticoid receptor function in vitro by modulating the membrane steroid transporters Br J Pharmacol 134 1335 1343 11704655 PMC1573058 sourceExperimental — accuracy not yet measured
The Discussion reports that clomipramine, citalopram, and paroxetine increased GR-mediated gene transcription in the presence of dexamethasone. It says fluoxetine had no such effect; the Results likewise report no potentiation with fluoxetine. The claim is therefore supported for three of the four named drugs, but not fluoxetine. (LLM, conf=0.89)
boosteddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“data also indicate that antidepressants exhibit the capacity to inhibit cytokine production both in vitro and in vivo.105”
§ Cytokines and Glucocorticoid Receptor Signaling > Treatment Implications > Antidepressants
What the sources say
- Supportedcites [105] Kenis G Maes M 2002 Effects of antidepressants on the production of cytokines Int J Neuropsychopharmacol 5 401 412 12466038 source
The in-vitro section reports that several antidepressants decreased stimulated production of pro-inflammatory cytokines. The animal-models section concludes that chronic treatment with tricyclic antidepressants reduced production of TNF-α and IL-1β in vivo. The claim describes a capacity to inhibit cytokine production, not inhibition of every cytokine by every antidepressant. (LLM, conf=0.92)
hedgeddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“More clear evidence of a reciprocal relationship between inflammatory and glucocorticoid signaling pathways has recently been observed in a study of individuals exposed to the chronic stress of caring for a patient with brain cancer versus nonstressed, healthy control subjects.89”
§ Cytokines and Glucocorticoid Receptor Signaling > Relationship between Inflammation and GR Signaling in Major Depression and Stress
What the sources say
- Supportedcites [89] Miller G 2008 A functional genomic finger-print of chronic stress in humans: Blunted glucocorticoid and increased NF-kappaB signaling Biol Psychiatry 64 4 266 272 18440494 PMC2581622 source
Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Salivary cortisol levels collected over 3 consecutive days were no different between the groups.”
§ Cytokines and Glucocorticoid Receptor Signaling > Relationship between Inflammation and GR Signaling in Major Depression and Stress
What the sources say
- Partly supportedcites [89] Miller G 2008 A functional genomic finger-print of chronic stress in humans: Blunted glucocorticoid and increased NF-kappaB signaling Biol Psychiatry 64 4 266 272 18440494 PMC2581622 sourceExperimental — accuracy not yet measured
The Methods and Results say saliva was collected over three days and that caregivers and controls had similar overall cortisol patterns and total daily output. The Results also report higher cortisol in caregivers four hours after waking, so the unqualified statement that levels were no different is too broad. Page numbers are not available in the supplied passages. (LLM, conf=0.88)
plain- Asserted: passes — The authors put it forward as true.
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- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“cAMP and PKA signaling pathways also interact with cytokine signaling pathways, including NF-κB, MAPK and Jak-STAT pathways.114–116”
§ Cytokines and Glucocorticoid Receptor Signaling > Treatment Implications > PKA
What the sources say
- Not checked — no full text of the sourcecites [114] Takahashi E 2002 Expression of c-fos, rather than c-jun or glucocorticoid-receptor mRNA, correlates with decreased glucocorticoid response of peripheral blood mononuclear cells in asthma Int Immunopharmacol 2 1419 1427 12400872 source
- Not checked — no full text of the sourcecites [115] Saxena M 1999 Crosstalk between cAMP-dependent kinase and MAP kinase through a protein tyrosine phosphatase Nat Cell Biol 1 305 311 10559944 source
- Partly supportedcites [116] Sengupta T Schmitt E Ivashkiv L 1996 Inhibition of cytokines and JAK-STAT activation by distinct signaling pathways Proc Natl Acad Sci USA 93 9499 9504 8790359 PMC38457 sourceExperimental — accuracy not yet measured
The Abstract (page not specified in our copy) reports that cAMP interrupts cytokine-triggered JAK–STAT signaling. It does not establish interactions with NF-κB or MAPK; PKA appears in a cited reference concerning JAK–STAT, rather than in the paper’s reported findings. (LLM, conf=0.86)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Every source the paper cites for this claim was checked and supports it.
In the paper
“A number of studies have shown that the PKA signaling pathway plays an essential role in GR function.”
§ Cytokines and Glucocorticoid Receptor Signaling > Treatment Implications > PKA
What the sources say
- Supportedcites [107] Doucas V 2000 Cytoplasmic catalytic subunit of protein kinase A mediates cross-repression by NF-kappa B and the glucocorticoid receptor Proc Natl Acad Sci USA 97 11893 11898 11027313 PMC17265 source
The Abstract states that GR transcription depends on PKA signaling. The Results further report that inhibiting PKA reduced GR-dependent transcription, supporting the claimed role of the pathway in GR function. (LLM, conf=0.90)
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“the PKA activator forskolin inhibits MAPK-induced raf-1 translocation118”
§ Cytokines and Glucocorticoid Receptor Signaling > Treatment Implications > PKA
What the sources say
- Partly supportedcites [118] Melck D 1999 Involvement of the cAMP/protein kinase A pathway and of mitogen-activated protein kinase in the anti-proliferative effects of anandamide in human breast cancer cells FEBS Lett 463 235 240 10606728 sourceExperimental — accuracy not yet measured
Section 3.3 reports that forskolin prevented anandamide (ANA)-induced Raf-1 translocation in MCF-7 cells. It does not describe the translocation as MAPK-induced; instead, it reports ANA-induced Raf-1 translocation alongside MAPK activation. Page numbers are not provided in our copy's passages. (LLM, conf=0.85)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“These data, which capitalize on the advantages of state-of-the-art microarray and bioinformatics technology, provide compelling evidence that in the context of stress, the balance between the neuroendocrine and immune systems is clearly tipped toward increased inflammatory signaling at the expense of a decrease in GR signaling.”
§ Cytokines and Glucocorticoid Receptor Signaling > Relationship between Inflammation and GR Signaling in Major Depression and Stress
What the sources say
- Supportedcites [89] Miller G 2008 A functional genomic finger-print of chronic stress in humans: Blunted glucocorticoid and increased NF-kappaB signaling Biol Psychiatry 64 4 266 272 18440494 PMC2581622 source
The Results report that caregivers’ monocytes showed diminished glucocorticoid-responsive transcription and heightened NF-κB-responsive transcription compared with controls. The Discussion interprets this pattern as chronic stress fostering pro-inflammatory signaling through reduced glucocorticoid signaling. The evidence is specifically from a chronic-stress caregiver comparison. (LLM, conf=0.92)
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Studies investigating the mechanisms by which antidepressants exert their effects suggest that cAMP and PKA pathways act as mediators of the psychotropic effects of these agents (e.g., Nibuya et al.122).”
§ Cytokines and Glucocorticoid Receptor Signaling > Treatment Implications > PKA
What the sources say
- Supportedcites Nibuya et al. [122] Nibuya M Nestler E Duman R 1996 Chronic antidepressant administration increases the expression of cAMP response element binding protein (CREB) in rat hippocampus J Neurosci 16 2365 2372 8601816 PMC6578518 source
The introductory passages describe CREB as a possible mediator of long-term antidepressant adaptations and explain that cAMP-dependent protein kinase (PKA) activates it. The paper also says previous studies support a role for the cAMP cascade in antidepressants’ long-term actions. That supports the citing sentence’s hedged claim; the passages do not provide page numbers. (LLM, conf=0.88)
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“PKA also activates GR function in a ligand-independent manner.111”
§ Cytokines and Glucocorticoid Receptor Signaling > Treatment Implications > PKA
What the sources say
- Partly supportedcites [111] Eickelberg O 1999 Ligand-independent activation of the glucocorticoid receptor by beta2-adrenergic receptor agonists in primary human lung fibroblasts and vascular smooth muscle cells J Biol Chem 274 1005 1010 9873044 sourceExperimental — accuracy not yet measured
The Discussion (p. 5) demonstrates ligand-independent, functional GR activation by β2-adrenergic agonists. The Results (p. 4) report that a PKA-inhibiting peptide partly reduced this activation, and the Discussion (p. 6) describes PKA-pathway involvement as possible rather than establishing that PKA itself activates GR. (LLM, conf=0.87)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“GR and the catalytic subunit of PKA have been found to associate in a ligand-independent manner both in vivo and in vitro.107”
§ Cytokines and Glucocorticoid Receptor Signaling > Treatment Implications > PKA
What the sources say
- Supportedcites [107] Doucas V 2000 Cytoplasmic catalytic subunit of protein kinase A mediates cross-repression by NF-kappa B and the glucocorticoid receptor Proc Natl Acad Sci USA 97 11893 11898 11027313 PMC17265 source
The Results section ('GR Associates with PKAc in Vitro and in Vivo'; page unavailable) reports that GR binds PKAc in vitro both with and without dexamethasone, and that PKAc coprecipitates with GR in cells. A further Results passage reports GR interference with PKAc–RelA association in vivo both with and without dexamethasone, consistent with ligand-independent association. (LLM, conf=0.88)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
In the paper
“Subsequent studies examining the signal transduction mechanisms responsible for these effects revealed that IL-1-α induction of p38 MAPK was involved, given that antisense oligonucleotides targeting p38 were able to reverse the effects of IL-1-α on DEX-induced, GR-mediated gene transcription.44”
§ Cytokines and Glucocorticoid Receptor Signaling > Cytokine Effects on GR Function
What the sources say
- Not checked — no full text of the sourcecites [44] Wang X Wu H Miller A 2004 Interleukin 1α (IL-1α) induced activation of p38 mitogen-activated protein kinase inhibits glucocorticoid receptor function Mol Psychiatry 9 65 75 14699442 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“studies from our group have found that treatment of rat PC12 cells with the COX-1 and COX-2 inhibitor, ibuprofen, or the selective COX-2 inhibitor, celecoxib, significantly increased GR-mediated gene transcription.”
§ Cytokines and Glucocorticoid Receptor Signaling > Cytokine Effects on GR Function
What the sources say
- Not checked — no full text of the sourcecites [49] Irusen E 2002 p38 Mitogen-activated protein kinase-induced glucocorticoid receptor phosphorylation reduces its activity: role in steroid-insensitive asthma J Allergy Clin Immunol 109 649 657 11941315 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Effects were reversed by co-administration of IL-1 receptor antagonist (IL-1ra).”
§ Cytokines and Glucocorticoid Receptor Signaling > Cytokine Effects on GR Function
What the sources say
- Not checked — no full text of the sourcecites [43] Pariante C 1999 The proinflammatory cytokine, interleukin-1α, reduces glucocorticoid receptor translocation and function Endocrinology 140 4359 4366 10465310 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Using a mouse L929 fibroblast cell line, administration of IL-1-α was found to induce a significant decrease in DEX-induced GR translocation from cytoplasm to nucleus that was associated with decreased GR-DNA binding and decreased DEX-induced activation of a reporter gene construct with multiple glucocorticoid response elements (GRE) upstream of its promoter region.43”
§ Cytokines and Glucocorticoid Receptor Signaling > Cytokine Effects on GR Function
What the sources say
- Not checked — no full text of the sourcecites [43] Pariante C 1999 The proinflammatory cytokine, interleukin-1α, reduces glucocorticoid receptor translocation and function Endocrinology 140 4359 4366 10465310 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“we administered anisomycin, a potent activator of p38, along with celecoxib to rat PC12 cells. Anisomycin reversed the celecoxib-induced enhancement of GR-mediated gene transcription in a dose-dependent manner, indicating the effects of COX-2 inhibitors on GR may be related to inhibition of p38.49”
§ Cytokines and Glucocorticoid Receptor Signaling > Cytokine Effects on GR Function
What the sources say
- Not checked — no full text of the sourcecites [49] Irusen E 2002 p38 Mitogen-activated protein kinase-induced glucocorticoid receptor phosphorylation reduces its activity: role in steroid-insensitive asthma J Allergy Clin Immunol 109 649 657 11941315 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“IL-1-α treatment was also associated with significant upregulation of GR protein that was primarily apparent in the cytosolic compartment.43”
§ Cytokines and Glucocorticoid Receptor Signaling > Cytokine Effects on GR Function
What the sources say
- Not checked — no full text of the sourcecites [43] Pariante C 1999 The proinflammatory cytokine, interleukin-1α, reduces glucocorticoid receptor translocation and function Endocrinology 140 4359 4366 10465310 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“the same studies found that the selective COX-1 inhibitor, valerylsalicylic acid, had no effects on GR function.49”
§ Cytokines and Glucocorticoid Receptor Signaling > Cytokine Effects on GR Function
What the sources say
- Not checked — no full text of the sourcecites [49] Irusen E 2002 p38 Mitogen-activated protein kinase-induced glucocorticoid receptor phosphorylation reduces its activity: role in steroid-insensitive asthma J Allergy Clin Immunol 109 649 657 11941315 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“We found that the PDE type IV inhibitor, rolipram, which antagonizes the breakdown of cAMP, significantly enhanced GR-mediated gene transcription in LMCAT mouse fibroblast cells and rat C6 glioma cells, both in the presence and absence of DEX.”
§ Cytokines and Glucocorticoid Receptor Signaling > Treatment Implications > PKA
What the sources say
- Not checked — no full text of the sourcecites [71] Miller A Vogt G Pearce B 2002 The phosphodiesterase type 4 inhibitor, rolipram, enhances glucocorticoid receptor function Neuropsychopharmacology 27 939 948 12464451 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“This effect was independent of the p-glycoprotein pump.71”
§ Cytokines and Glucocorticoid Receptor Signaling > Treatment Implications > PKA
What the sources say
- Not checked — no full text of the sourcecites [71] Miller A Vogt G Pearce B 2002 The phosphodiesterase type 4 inhibitor, rolipram, enhances glucocorticoid receptor function Neuropsychopharmacology 27 939 948 12464451 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Statistical analyses revealed that cortisol values in the evening were significantly higher in IFN-α–treated subjects compared to controls”
§ Cytokines and Glucocorticoid Receptor Signaling > IFN-α as a Model System to Study HPA-Immune Interactions in Depression
What the sources say
- Not checked — no full text of the sourcecites [93] Raison C 2008 Interferon-alpha effects on diurnal hypothalamic-pituitary-adrenal axis activity: relationship with proinflammatory cytokines and behavior Mol Psychiatry 3 6 10.1038/mp.2008.58 PMC3403676 18521089 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Interestingly, patients who received IFN-α treatment exhibited significant flattening of the cortisol curve compared to non-IFN-α–treated controls (Fig. 4).93”
§ Cytokines and Glucocorticoid Receptor Signaling > IFN-α as a Model System to Study HPA-Immune Interactions in Depression
What the sources say
- Not checked — no full text of the sourcecites [93] Raison C 2008 Interferon-alpha effects on diurnal hypothalamic-pituitary-adrenal axis activity: relationship with proinflammatory cytokines and behavior Mol Psychiatry 3 6 10.1038/mp.2008.58 PMC3403676 18521089 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“like the flattened cortisol curve, increases in evening cortisol concentrations over the course of the study were associated with increased symptoms of depression and fatigue.”
§ Cytokines and Glucocorticoid Receptor Signaling > IFN-α as a Model System to Study HPA-Immune Interactions in Depression
What the sources say
- Not checked — no full text of the sourcecites [93] Raison C 2008 Interferon-alpha effects on diurnal hypothalamic-pituitary-adrenal axis activity: relationship with proinflammatory cytokines and behavior Mol Psychiatry 3 6 10.1038/mp.2008.58 PMC3403676 18521089 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“In addition, flattening of the cortisol curve was found to significantly correlate with the development of depressive symptoms, as well as fatigue, in these subjects.”
§ Cytokines and Glucocorticoid Receptor Signaling > IFN-α as a Model System to Study HPA-Immune Interactions in Depression
What the sources say
- Not checked — no full text of the sourcecites [93] Raison C 2008 Interferon-alpha effects on diurnal hypothalamic-pituitary-adrenal axis activity: relationship with proinflammatory cytokines and behavior Mol Psychiatry 3 6 10.1038/mp.2008.58 PMC3403676 18521089 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Of note, the degree of difference between cortisol slopes in IFN-α–treated versus nontreated subjects was similar to those differences reported in the literature of various clinical populations.93”
§ Cytokines and Glucocorticoid Receptor Signaling > IFN-α as a Model System to Study HPA-Immune Interactions in Depression
What the sources say
- Not checked — no full text of the sourcecites [93] Raison C 2008 Interferon-alpha effects on diurnal hypothalamic-pituitary-adrenal axis activity: relationship with proinflammatory cytokines and behavior Mol Psychiatry 3 6 10.1038/mp.2008.58 PMC3403676 18521089 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Rates of DEX nonsuppression in depressed patients range from 25% to 80% depending on a number of factors, including age, sex, severity of depression, and the type of test employed”
§ Cytokines and Glucocorticoid Receptor Signaling > Glucocorticoid Resistance in Major Depression
What the sources say
- Not checked — no full text of the sourcecites [10] Raison C Miller A 2003 When not enough is too much: the role of insufficient glucocorticoid signaling in the pathophysiology of stress-related disorders Am J Psychiatry 160 1554 1565 12944327 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“suggesting that drugs that target both inflammatory responses and the GR may have special efficacy in the treatment of depression.”
§ Cytokines and Glucocorticoid Receptor Signaling > Abstract
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Patients with major depression have been found to exhibit increased biomarkers of inflammation in both the peripheral blood and cerebrospinal fluid (CSF).6”
§ Cytokines and Glucocorticoid Receptor Signaling > Introduction
What the sources say
- Not checked — no full text of the sourcecites [6] Raison C Capuron L Miller A 2006 Cytokines sing the blues: inflammation and the pathogenesis of depression Trends Immunol 27 24 31 16316783 PMC3392963 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Probably the most reliable finding in this regard is nonsuppression of ACTH or cortisol secretion following administration of the synthetic glucocorticoid, DEX in the presence or absence of CRF during the DEX suppression test (DST) or DEX-CRF test, respectively.10”
§ Cytokines and Glucocorticoid Receptor Signaling > Glucocorticoid Resistance in Major Depression
What the sources say
- Not checked — no full text of the sourcecites [10] Raison C Miller A 2003 When not enough is too much: the role of insufficient glucocorticoid signaling in the pathophysiology of stress-related disorders Am J Psychiatry 160 1554 1565 12944327 source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“in many depressed patients there is evidence of glucocorticoid resistance as manifested, for example, by dexamethasone (DEX) nonsuppression.7,8”
§ Cytokines and Glucocorticoid Receptor Signaling > Introduction
What the sources say
- Not checked — no full text of the sourcecites [7] Pariante C Miller A 2001 Glucocorticoid receptors in major depression: relevance to pathophysiology and treatment Biol Psychiatry 49 391 404 11274650 source
- Not checked — no full text of the sourcecites [8] Holsboer F 2000 The corticosteroid receptor hypothesis of depression Neuropsychopharmacology 23 477 501 11027914 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“cytokines have been shown to increase the expression of the relatively inert GR beta isoform.”
§ Cytokines and Glucocorticoid Receptor Signaling > Abstract
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“There is considerable evidence that glucocorticoid signaling is decreased in patients with major depression.”
§ Cytokines and Glucocorticoid Receptor Signaling > Glucocorticoid Resistance in Major Depression
What the sources say
- Not checked — no full text of the sourcecites [10] Raison C Miller A 2003 When not enough is too much: the role of insufficient glucocorticoid signaling in the pathophysiology of stress-related disorders Am J Psychiatry 160 1554 1565 12944327 source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Data suggest that the activation of immune responses and the release of inflammatory cytokines may play a role in the pathophysiology of major depression.”
- Also stated in: § Introduction · hedged
“there has been growing interest in the notion that inflammation and activation of the innate immune response may play a role in neuropsychiatric disorders, including major depression.”
§ Cytokines and Glucocorticoid Receptor Signaling > Abstract
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § Introduction · hedged
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“p38 mitogen-activated protein kinase, which is associated with reduced GR translocation”
§ Cytokines and Glucocorticoid Receptor Signaling > Abstract
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“cytokines have been shown to decrease GR expression”
§ Cytokines and Glucocorticoid Receptor Signaling > Abstract
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Antidepressants and PKA activation have also been found to inhibit inflammatory cytokines and their signaling pathways”
§ Cytokines and Glucocorticoid Receptor Signaling > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“several antidepressants have been shown to enhance GR function”
§ Cytokines and Glucocorticoid Receptor Signaling > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“cortisol is one of the most potent anti-inflammatory hormones in the body.9”
§ Cytokines and Glucocorticoid Receptor Signaling > Glucocorticoid Resistance in Major Depression
What the sources say
- Not checked — no full text of the sourcecites [9] Rhen T Cidlowski J 2005 Antiinflammatory action of glucocorticoids—new mechanisms for old drugs N Engl J Med 353 1711 1723 16236742 source
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“disrupt GR-DNA binding through nuclear protein-protein interactions”
§ Cytokines and Glucocorticoid Receptor Signaling > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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In the paper
“increased concentrations of innate immune cytokines, including interleukin (IL)-1, IL-6 and tumor necrosis factor (TNF)-α, as well as their soluble receptors, have been found in the peripheral blood and/or CSF of depressed patients.6”
§ Cytokines and Glucocorticoid Receptor Signaling > Inflammation and Major Depression
What the sources say
- Not checked — no full text of the sourcecites [6] Raison C Capuron L Miller A 2006 Cytokines sing the blues: inflammation and the pathogenesis of depression Trends Immunol 27 24 31 16316783 PMC3392963 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Nuclear factor-κB (NF-κB) also has been shown to lead to GR suppression through mutually inhibitory GR-NF-κB nuclear interactions.”
§ Cytokines and Glucocorticoid Receptor Signaling > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“although glucocorticoids (i.e., cortisol) may be elevated in patients with major depression, they appear to fail to inhibit inflammatory responses by virtue of insufficient glucocorticoid signaling.10”
§ Cytokines and Glucocorticoid Receptor Signaling > Introduction
What the sources say
- Not checked — no full text of the sourcecites [10] Raison C Miller A 2003 When not enough is too much: the role of insufficient glucocorticoid signaling in the pathophysiology of stress-related disorders Am J Psychiatry 160 1554 1565 12944327 source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“innate immune cytokines are potent stimulators of the neuroregulatory peptide corticotropin-releasing factor (CRF).31”
§ Cytokines and Glucocorticoid Receptor Signaling > Inflammation and Major Depression
What the sources say
- Not checked — no full text of the sourcecites [31] Besedovsky H del Rey A 1996 Immune-neuroendocrine interactions: facts and hypotheses Endocr Rev 17 64 102 8641224 source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“One mechanism by which cytokines may contribute to depression is through their effects on the glucocorticoid receptor (GR).”
§ Cytokines and Glucocorticoid Receptor Signaling > Abstract
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“block translocation of the GR from cytoplasm to nucleus”
§ Cytokines and Glucocorticoid Receptor Signaling > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“signal transducer and activator of transcription (STAT)5, which binds to GR in the nucleus”
§ Cytokines and Glucocorticoid Receptor Signaling > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“the relative expression of hGR-α and hGR-β is believed to contribute to conditions of glucocorticoid resistance in disorders, such as glucocorticoid-resistant asthma, leukemia, ulcerative colitis, and rheumatoid arthritis.74”
§ Cytokines and Glucocorticoid Receptor Signaling > Cytokine Effects on GR Function
What the sources say
- Not checked — no full text of the sourcecites [74] Lewis-Tuffin L Cidlowski J 2006 The physiology of human glucocorticoid receptor beta (hGR-beta) and glucocorticoid resistance Ann N Y Acad Sci 1069 1 9 16855130 source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“cytokine-induced decreases in CBG are believed to play a role in the decreased levels of CBG seen in septic shock and burn patients.81,82”
§ Cytokines and Glucocorticoid Receptor Signaling > Cytokine Effects on GR Function
What the sources say
- Not checked — no full text of the sourcecites [81] Bernier J 1998 Decreased corticosteroid-binding globulin in burn patients: relationship with interleukin-6 and fat in nutritional support Crit Care Med 26 452 460 9504571 source
- Not checked — no full text of the sourcecites [82] Emptoz-Bonneton A 1997 Corticosteroid-binding globulin synthesis regulation by cytokines and glucocorticoids in human hepatoblastoma-derived (HepG2) cells J Clin Endocrinol Metab 82 3758 3762 9360537 source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“There are two isoforms of the GR in humans, human (h)GR-α and hGR-β.74”
§ Cytokines and Glucocorticoid Receptor Signaling > Cytokine Effects on GR Function
What the sources say
- Not checked — no full text of the sourcecites [74] Lewis-Tuffin L Cidlowski J 2006 The physiology of human glucocorticoid receptor beta (hGR-beta) and glucocorticoid resistance Ann N Y Acad Sci 1069 1 9 16855130 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“chronic administration of endotoxin was associated with the development of DEX nonsuppression in rats41”
§ Cytokines and Glucocorticoid Receptor Signaling > Cytokine Effects on GR Function
What the sources say
- Not checked — no full text of the sourcecites [41] Weidenfeld J Yirmiya R 1996 Effects of bacterial endotoxin on the glucocorticoid feedback regulation of adrenocortical response to stress Neuroimmunomodulation 3 352 357 9266546 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“one of the earliest studies in this regard showed a significant correlation between post-DEX concentrations of cortisol and the production of IL-1 by peripheral blood mononuclear cells.85”
§ Cytokines and Glucocorticoid Receptor Signaling > Relationship between Inflammation and GR Signaling in Major Depression and Stress
What the sources say
- Not checked — no full text of the sourcecites [85] Maes M 1993 Interleukin-1 beta: a putative mediator of HPA axis hyperactivity in major depression? Am J Psychiatry 150 1189 1193 8328562 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Additional mechanisms that may be involved in STAT5-induced inhibition of GR function are believed to include disruption of GR translocation.56”
§ Cytokines and Glucocorticoid Receptor Signaling > Cytokine Effects on GR Function
What the sources say
- Not checked — no full text of the sourcecites [56] Onda K 2006 Mitogen-activated protein kinase kinase 1/extracellular signal-regulated kinase (MEK-1/ERK) inhibitors sensitize reduced glucocorticoid response mediated by TNFα in human epidermal keratinocytes (HaCaT) Biochem Biophys Res Commun 351 266 272 17054908 source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Increased in vitro sensitivity of innate immune responses to glucocorticoids was also found in depressed patients prior to a laboratory stressor”
§ Cytokines and Glucocorticoid Receptor Signaling > Relationship between Inflammation and GR Signaling in Major Depression and Stress
What the sources say
- Not checked — no full text of the sourcecites [87] Miller G 2005 Clinical depression and regulation of the inflammatory response during acute stress Psychosom Med 67 679 687 16204423 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Taken together, these results suggest that MAPK signaling pathways (including both p38 and JNK) may be involved in the effects of COX-2 inhibition on GR function.”
§ Cytokines and Glucocorticoid Receptor Signaling > Cytokine Effects on GR Function
What the sources say
- Not checked — no full text of the sourcecites [49] Irusen E 2002 p38 Mitogen-activated protein kinase-induced glucocorticoid receptor phosphorylation reduces its activity: role in steroid-insensitive asthma J Allergy Clin Immunol 109 649 657 11941315 source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“NF-κB has been found to directly interact with GR in the nucleus through protein-protein interactions, causing mutual repression of both GR and NF-κB function.67”
§ Cytokines and Glucocorticoid Receptor Signaling > Cytokine Effects on GR Function
What the sources say
- Not checked — no full text of the sourcecites [67] McKay L Cidlowski J 1999 Molecular control of immune/inflammatory responses: interactions between nuclear factor-kappa B and steroid receptor-signaling pathways Endocr Rev 20 435 459 10453354 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“hGR-β has been found to limit the activity of hGR-α as a transcription factor.74”
§ Cytokines and Glucocorticoid Receptor Signaling > Cytokine Effects on GR Function
What the sources say
- Not checked — no full text of the sourcecites [74] Lewis-Tuffin L Cidlowski J 2006 The physiology of human glucocorticoid receptor beta (hGR-beta) and glucocorticoid resistance Ann N Y Acad Sci 1069 1 9 16855130 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“an effect that is eliminated (along with glucocorticoid resistance) in gene-targeted mice in which the IL-1 receptor gene has been knocked out.61”
§ Cytokines and Glucocorticoid Receptor Signaling > Cytokine Effects on GR Function
What the sources say
- Not checked — no full text of the sourcecites [61] Engler H 2008 Interleukin-1 receptor type 1-deficient mice fail to develop social stress-associated glucocorticoid resistance in the spleen Psychoneuroendocrinology 33 108 117 18037570 PMC2701260 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“Social disruption stress in mice has been shown to lead to glucocorticoid resistance in splenic monocytes that is associated with increased susceptibility to the lethal effects of inflammatory stimuli, including endotoxic shock and pulmonary virus infection.58,59”
§ Cytokines and Glucocorticoid Receptor Signaling > Cytokine Effects on GR Function
What the sources say
- Not checked — no full text of the sourcecites [58] Quan N 2001 Social stress increases the susceptibility to endotoxic shock J Neuroimmunol 115 36 45 11282152 source
- Not checked — no full text of the sourcecites [59] Sheridan J 2000 Social disruption, immunity, and susceptibility to viral infection. Role of glucocorticoid insensitivity and NGF Ann N Y Acad Sci 917 894 905 11270350 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Several innate immune cytokines have been shown to increase the activity of 11β-HSD type 2, which inactivates cortisol, thereby increasing the availability of glucocorticoids.80”
§ Cytokines and Glucocorticoid Receptor Signaling > Cytokine Effects on GR Function
What the sources say
- Not checked — no full text of the sourcecites [80] Kossintseva I 2006 Proinflammatory cytokines inhibit human placental 11beta-hydroxysteroid dehydrogenase type 2 activity through Ca2+ and cAMP pathways Am J Physiol Endocrinol Metab 290 E282 288 16174654 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“GR and NF-κB have also been shown to compete with one another for the coactivators steroid receptor coactivator-1 (SRC-1) and CBP in the nucleus.68”
§ Cytokines and Glucocorticoid Receptor Signaling > Cytokine Effects on GR Function
What the sources say
- Not checked — no full text of the sourcecites [68] Sheppard K 1998 Nuclear integration of glucocorticoid receptor and nuclear factor-kappaB signaling by CREB-binding protein and steroid receptor coactivator-1 J Biol Chem 273 29291 29294 9792627 source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Jak-STAT activation has also been found to decrease GR function through effects on various cofactors including CREB binding protein (CBP) as well as through direct GR-STAT protein-protein interactions.66”
§ Cytokines and Glucocorticoid Receptor Signaling > Cytokine Effects on GR Function
What the sources say
- Not checked — no full text of the sourcecites [66] Rogatsky I Ivashkiv L 2006 Glucocoritcoid modulation of cytokine signaling Tissue Antigens 68 1 12 16774534 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
None of the sources cited for this claim could be matched to a paper in Crossref, so there is nothing to check it against.
In the paper
“These results are consistent with a number of studies that have shown that cytokine induction of p38 MAPK can directly influence GR function, including GR nuclear translocation, in part through GR phosphorylation (Table 1, Fig. 2).”
§ Cytokines and Glucocorticoid Receptor Signaling > Cytokine Effects on GR Function
What the sources say
- Not matchedcites Table 1
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not matchedcites Fig. 2
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Not matched
In the paper
“the mechanism of glucocorticoid resistance in socially disrupted mice involves decreased GR translocation from cytoplasm to nucleus,60”
§ Cytokines and Glucocorticoid Receptor Signaling > Cytokine Effects on GR Function
What the sources say
- Not checked — no full text of the sourcecites [60] Quan N 2003 Molecular mechanisms of glucocorticoid resistance in splenocytes of socially stressed male mice J Neuroimmunol 137 51 58 12667647 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Studies using immunoprecipitation have demonstrated that STAT5 and GR form complexes in the nucleus that ultimately disrupt GR-DNA binding (Fig. 2).”
§ Cytokines and Glucocorticoid Receptor Signaling > Cytokine Effects on GR Function
What the sources say
- Not checked — no full text of the sourcecites [56] Onda K 2006 Mitogen-activated protein kinase kinase 1/extracellular signal-regulated kinase (MEK-1/ERK) inhibitors sensitize reduced glucocorticoid response mediated by TNFα in human epidermal keratinocytes (HaCaT) Biochem Biophys Res Commun 351 266 272 17054908 source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“subjects with evidence of glucocorticoid resistance (as manifested by increased ACTH and cortisol responses) exhibited increased cytokine (IL-6 and TNF-α) responses regardless of whether they were depressed or not”
§ Cytokines and Glucocorticoid Receptor Signaling > Relationship between Inflammation and GR Signaling in Major Depression and Stress
What the sources say
- Not checked — no full text of the sourcecites [88] Vedder H 2007 Immune-endocrine host response to endotoxin in major depression J Psychiatr Res 41 280 289 17045296 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“in the case of the DEX-CRF test, there is evidence that impaired glucocorticoid responsiveness represents a genetically based risk factor for the development of depression.10”
§ Cytokines and Glucocorticoid Receptor Signaling > Glucocorticoid Resistance in Major Depression
What the sources say
- Not checked — no full text of the sourcecites [10] Raison C Miller A 2003 When not enough is too much: the role of insufficient glucocorticoid signaling in the pathophysiology of stress-related disorders Am J Psychiatry 160 1554 1565 12944327 source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“Cytokines, including IL-6, have been shown to inhibit CBG production”
§ Cytokines and Glucocorticoid Receptor Signaling > Cytokine Effects on GR Function
What the sources say
- Not checked — no full text of the sourcecites [81] Bernier J 1998 Decreased corticosteroid-binding globulin in burn patients: relationship with interleukin-6 and fat in nutritional support Crit Care Med 26 452 460 9504571 source
- Not checked — no full text of the sourcecites [82] Emptoz-Bonneton A 1997 Corticosteroid-binding globulin synthesis regulation by cytokines and glucocorticoids in human hepatoblastoma-derived (HepG2) cells J Clin Endocrinol Metab 82 3758 3762 9360537 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“indicating the effects of COX-2 inhibitors on GR may be related to inhibition of p38.49”
§ Cytokines and Glucocorticoid Receptor Signaling > Cytokine Effects on GR Function
What the sources say
- Not checked — no full text of the sourcecites [49] Irusen E 2002 p38 Mitogen-activated protein kinase-induced glucocorticoid receptor phosphorylation reduces its activity: role in steroid-insensitive asthma J Allergy Clin Immunol 109 649 657 11941315 source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“ERK activation has been found to mediate super-antigen–induced corticosteroid resistance in human T cells.64”
§ Cytokines and Glucocorticoid Receptor Signaling > Cytokine Effects on GR Function
What the sources say
- Not checked — no full text of the sourcecites [64] Li L 2004 Superantigen-induced corticosteroid resistance of human T cells occurs through activation of the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK-ERK) pathway J Allergy Clin Immunol 114 1059 1069 15536411 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Results from these largely cross-sectional studies have been mixed with some studies reporting a limited association between glucocorticoid resistance and increased markers of inflammation, while others have reported a clear association between these variables.”
§ Cytokines and Glucocorticoid Receptor Signaling > Relationship between Inflammation and GR Signaling in Major Depression and Stress
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“As noted above, COX-2 inhibitors have been shown to enhance GR function (DEX-induced GR-mediated reporter gene activity and GR-GRE binding)”
§ Cytokines and Glucocorticoid Receptor Signaling > Treatment Implications > COX-2 Inhibitors
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“COX-2 inhibitors were found to augment the effects of the antidepressant reboxetine in treating patients with major depression.123”
§ Cytokines and Glucocorticoid Receptor Signaling > Treatment Implications > COX-2 Inhibitors
What the sources say
- Not checked — no full text of the sourcecites [123] Muller N 2006 The cyclooxygenase-2 inhibitor celecoxib has therapeutic effects in major depression: results of a double-blind, randomized, placebo controlled, add-on pilot study to reboxetine Mol Psychiatry 11 680 684 16491133 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“In addition to direct effects on GR function, increased PKA activity has also been found to reverse GR resistance.”
§ Cytokines and Glucocorticoid Receptor Signaling > Treatment Implications > PKA
What the sources say
- Not checked — no full text of the sourcecites [112] Medh R 1998 Resistance of human leukemic CEM-C1 cells is overcome by synergism between glucocorticoid and protein kinase A pathways: correlation with c-Myc suppression Cancer Res 58 3684 3693 9721879
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“the degree of HPA axis responsiveness to IFN-α in terms of both ACTH and cortisol was found to correlate with the severity of depressive symptoms during IFN-α therapy.”
§ Cytokines and Glucocorticoid Receptor Signaling > IFN-α as a Model System to Study HPA-Immune Interactions in Depression
What the sources say
- Not checked — no full text of the sourcecites [96] Capuron L 2003 Association of exaggerated HPA axis response to the initial injection of interferon-alpha with development of depression during interferon-alpha therapy Am J Psychiatry 160 1342 1345 12832253 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“For example, amitriptyline decreased LPS-stimulated release of IL-1-β and TNF-α from a mixed glial culture.106”
§ Cytokines and Glucocorticoid Receptor Signaling > Treatment Implications > Antidepressants
What the sources say
- Not checked — no full text of the sourcecites [106] Obuchowicz E 2006 Amitriptyline and nortriptyline inhibit interleukin-1 release by rat mixed glial and microglial cell cultures Int J Neuropsychopharmacol 9 27 35 15963243 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Taken together, these findings support the hypothesis that increased innate immune cytokines may contribute to glucocorticoid resistance in major depression.”
§ Cytokines and Glucocorticoid Receptor Signaling > Summary
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Therefore, it is possible that disruption in the cAMP/PKA pathway in major depression is linked to cytokine-induced glucocorticoid resistance.”
§ Cytokines and Glucocorticoid Receptor Signaling > Treatment Implications > PKA
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Cyclic AMP/PKA signal transduction pathways are reduced in postmortem brain tissue from depressed patients.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“both of which have been implicated in the disruption of GR function (see above).”
§ Cytokines and Glucocorticoid Receptor Signaling > IFN-α as a Model System to Study HPA-Immune Interactions in Depression
plaincorrelational- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“IFN-α acutely activates the HPA axis in humans, stimulating dramatic increases in ACTH and cortisol within several hours.95,96”
§ Cytokines and Glucocorticoid Receptor Signaling > IFN-α as a Model System to Study HPA-Immune Interactions in Depression
What the sources say
- Not checked yetcites [95] Gisslinger H 1993 Interferon-alpha stimulates the hypothalamic-pituitary-adrenal axis in vivo and in vitro Neuroendocrinology 57 489 495 8391662
- Not checked — no full text of the sourcecites [96] Capuron L 2003 Association of exaggerated HPA axis response to the initial injection of interferon-alpha with development of depression during interferon-alpha therapy Am J Psychiatry 160 1342 1345 12832253 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the effects of cytokines on glucocorticoid signaling and the brain may in turn contribute to the pathophysiology of depression in some depressed patients.”
§ Cytokines and Glucocorticoid Receptor Signaling > Summary
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“and bespeak involvement of alterations in glucocorticoid sensitivity to feedback inhibition, potentially mediated by cytokine effects on the GR.”
§ Cytokines and Glucocorticoid Receptor Signaling > IFN-α as a Model System to Study HPA-Immune Interactions in Depression
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“No differences were found in IL-6 responses between those who became depressed and those who did not.”
§ Cytokines and Glucocorticoid Receptor Signaling > IFN-α as a Model System to Study HPA-Immune Interactions in Depression
What the sources say
- Not checked — no full text of the sourcecites [96] Capuron L 2003 Association of exaggerated HPA axis response to the initial injection of interferon-alpha with development of depression during interferon-alpha therapy Am J Psychiatry 160 1342 1345 12832253 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These data suggest that feedback inhibition of cortisol secretion late in the day may be disrupted as a function of IFN-α treatment”
§ Cytokines and Glucocorticoid Receptor Signaling > IFN-α as a Model System to Study HPA-Immune Interactions in Depression
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“depressed patients have been found to exhibit reduced G protein function in mononuclear cells.120”
§ Cytokines and Glucocorticoid Receptor Signaling > Treatment Implications > PKA
What the sources say
- Not checked — no full text of the sourcecites [120] Avissar S 1997 Reduced G protein functions and immunoreactive levels in mononuclear leukocytes of patients with depression Am J Psychiatry 154 211 217 9016270 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“cultured fibroblasts collected from depressed patients have been shown to have reduced cAMP-dependent protein kinase activity.121”
§ Cytokines and Glucocorticoid Receptor Signaling > Treatment Implications > PKA
What the sources say
- Not checked — no full text of the sourcecites [121] Shelton R Mainer D Sulser F 1996 cAMP-dependent protein kinase activity in major depression Am J Psychiatry 153 1037 1042 8678172 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
In the paper
“cAMP-resistant cell lines have been shown to give rise to a significantly higher frequency of glucocorticoid-resistant cell variants.113”
§ Cytokines and Glucocorticoid Receptor Signaling > Treatment Implications > PKA
What the sources say
- Not checked — no full text of the sourcecites [113] Gruol D 1986 Isolation of new types of dexamethasone-resistant variants from a cAMP-resistant lymphoma J Steroid Biochem 24 255 258 3009978 source
boosteddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“indicating that the relationship between HPA axis sensitivity to glucocorticoids and responsiveness of the innate immune system may be unrelated to diagnosis.88”
§ Cytokines and Glucocorticoid Receptor Signaling > Relationship between Inflammation and GR Signaling in Major Depression and Stress
What the sources say
- Not checked — no full text of the sourcecites [88] Vedder H 2007 Immune-endocrine host response to endotoxin in major depression J Psychiatr Res 41 280 289 17045296 source
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“data indicate that cytokines and their signaling pathways can significantly decrease GR function and glucocorticoid signaling both in vitro and in vivo.”
§ Cytokines and Glucocorticoid Receptor Signaling > Summary
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“no relationship was found between depressive symptoms and cortisol responses to IFN-α after several weeks of treatment.96”
§ Cytokines and Glucocorticoid Receptor Signaling > IFN-α as a Model System to Study HPA-Immune Interactions in Depression
What the sources say
- Not checked — no full text of the sourcecites [96] Capuron L 2003 Association of exaggerated HPA axis response to the initial injection of interferon-alpha with development of depression during interferon-alpha therapy Am J Psychiatry 160 1342 1345 12832253 source
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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In the paper
“IFN-α causes marked depressive symptoms in a high percentage of patients, depending on the dose and route of administration.”
§ Cytokines and Glucocorticoid Receptor Signaling > IFN-α as a Model System to Study HPA-Immune Interactions in Depression
What the sources say
- Not checked — no full text of the sourcecites [97] Capuron L 2002 Neurobehavioral effects of interferon-alpha in cancer patients: phenomenology and paroxetine responsiveness of symptom dimensions Neuropsychopharmacology 26 643 652 11927189 source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“IFN-α is a potent inducer of other innate immune cytokines, including most notably IL-6 and to a lesser extent IL-1 and TNF-α and their soluble receptors.92,93”
§ Cytokines and Glucocorticoid Receptor Signaling > IFN-α as a Model System to Study HPA-Immune Interactions in Depression
What the sources say
- Not checked — no full text of the sourcecites [92] Taylor J Grossberg S 1998 The effects of interferon-alpha on the production and action of other cytokines Semin Oncol 25 23 29 9482537
- Not checked — no full text of the sourcecites [93] Raison C 2008 Interferon-alpha effects on diurnal hypothalamic-pituitary-adrenal axis activity: relationship with proinflammatory cytokines and behavior Mol Psychiatry 3 6 10.1038/mp.2008.58 PMC3403676 18521089 source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Taken together, these data suggest that drugs that can activate cAMP-PKA pathways, such as PDE type IV inhibitors, may represent an intriguing therapeutic strategy in reversing glucocorticoid resistance.”
§ Cytokines and Glucocorticoid Receptor Signaling > Treatment Implications > PKA
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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In the paper
“The effects of antidepressants on GR function have been shown to be related in part to their inhibitory effects on the p-glycoprotein pump, which would make more hormone available to activate GR.104”
§ Cytokines and Glucocorticoid Receptor Signaling > Treatment Implications > Antidepressants
What the sources say
- Not checked — no full text of the sourcecites [104] Yau J 2007 The antidepressant desipramine requires the ABCB1 (Mdr1)-type p-glycoprotein to upregulate the glucocorticoid receptor in mice Neuropsychopharmacology 32 2520 2529 17356567 source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“these effects can be blocked by administration of anisomycin.”
§ Cytokines and Glucocorticoid Receptor Signaling > Treatment Implications > COX-2 Inhibitors
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“As such, antidepressants and other pharmacologic agents that enhance PKA signaling may overcome GR alterations via a direct effect on crosstalk between these pathways.”
§ Cytokines and Glucocorticoid Receptor Signaling > Treatment Implications > PKA
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Cyclic AMP/PKA signal transduction pathways are reduced in postmortem brain tissue from depressed patients.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“and may be secondary to inhibitory effects of IFN-α on GR function.”
§ Cytokines and Glucocorticoid Receptor Signaling > IFN-α as a Model System to Study HPA-Immune Interactions in Depression
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: IFN-α activates Jak-STAT and p38 MAPK signaling pathways.
In the paper
“and inhibits T cell activation through the downregulation of MAPK pathways.119”
§ Cytokines and Glucocorticoid Receptor Signaling > Treatment Implications > PKA
What the sources say
- Not checked — no full text of the sourcecites [119] Tamir A Granot Y Isakov N 1996 Inhibition of T lymphocyte activation by cAMP is associated with down-regulation of two parallel mitogen-activated protein kinase pathways, the extracellular signal-related kinase and c-Jun N-terminal kinase J Immunol 157 1514 1522 8759733 source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Elevated PKA also inhibits MAPK pathways by phosphorylation of serine residues on raf-1, which leads to a reduced affinity of raf for Ras in a number of cell types.117”
§ Cytokines and Glucocorticoid Receptor Signaling > Treatment Implications > PKA
What the sources say
- Not checked — no full text of the sourcecites [117] Hafner S 1994 Mechanism of inhibition of Raf-1 by protein kinase A Mol Cell Biol 14 6696 6703 7935389 PMC359200 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“PKA has been shown to phosphorylate GR independent of the presence of relevant chaperone proteins (i.e., hsp90)”
§ Cytokines and Glucocorticoid Receptor Signaling > Treatment Implications > PKA
What the sources say
- Not checked — no full text of the sourcecites [108] Haske T Nakao M Moudgil V 1994 Phosphorylation of immunopurified rat liver glucocorticoid receptor by the catalytic subunit of cAMP-dependent protein kinase Mol Cell Biochem 132 163 171 7969099 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Pharmacologic therapies targeting PKA may represent a “double hit” on mechanisms driving glucocorticoid resistance, given that PKA pathways can both enhance GR function and inhibit inflammatory signaling.71”
§ Cytokines and Glucocorticoid Receptor Signaling > Treatment Implications > PKA
What the sources say
- Not checked — no full text of the sourcecites [71] Miller A Vogt G Pearce B 2002 The phosphodiesterase type 4 inhibitor, rolipram, enhances glucocorticoid receptor function Neuropsychopharmacology 27 939 948 12464451 source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“A variety of antidepressants have been shown to enhance GR translocation and function both in vivo and in vitro.7”
§ Cytokines and Glucocorticoid Receptor Signaling > Treatment Implications > Antidepressants
What the sources say
- Not checked — no full text of the sourcecites [7] Pariante C Miller A 2001 Glucocorticoid receptors in major depression: relevance to pathophysiology and treatment Biol Psychiatry 49 391 404 11274650 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Nevertheless, the data provide a clear indication that chronic exposure to innate immune cytokines leads to changes in neuroendocrine function in vivo that “map onto” changes in relevant clinical populations”
§ Cytokines and Glucocorticoid Receptor Signaling > IFN-α as a Model System to Study HPA-Immune Interactions in Depression
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“patients who developed major depression during IFN-α treatment were found to exhibit significantly higher ACTH and cortisol responses to the first injection of IFN-α compared to individuals who did not develop depression.96”
§ Cytokines and Glucocorticoid Receptor Signaling > IFN-α as a Model System to Study HPA-Immune Interactions in Depression
What the sources say
- Not checked — no full text of the sourcecites [96] Capuron L 2003 Association of exaggerated HPA axis response to the initial injection of interferon-alpha with development of depression during interferon-alpha therapy Am J Psychiatry 160 1342 1345 12832253 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“NF-kB transcription is blocked by increased PKA activity through interaction of the catalytic subunit of PKA with p65, which stops p65 transactivation114 (Fig. 2).”
§ Cytokines and Glucocorticoid Receptor Signaling > Treatment Implications > PKA
What the sources say
- Not checked — no full text of the sourcecites [114] Takahashi E 2002 Expression of c-fos, rather than c-jun or glucocorticoid-receptor mRNA, correlates with decreased glucocorticoid response of peripheral blood mononuclear cells in asthma Int Immunopharmacol 2 1419 1427 12400872 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- It may state two separate claims as one. 36
- Probably not a substantial claim. 8
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“hGR-β has recently been found to bind the GR antagonist, RU38486, and is transcriptionally active (even in the absence of ligand, similar to GR-α)”
§ Cytokines and Glucocorticoid Receptor Signaling > Cytokine Effects on GR Function
What the sources say
- Partly supportedcites [79] Lewis-Tuffin L 2007 Human glucocorticoid receptor beta binds RU-486 and is transcriptionally active Mol Cell Biol 27 2266 2282 17242213 PMC1820503 sourceExperimental — accuracy not yet measured
The Abstract reports that hGRβ binds RU-486, and the Discussion describes hGRβ as a ligand-independent regulator of gene expression (pages not provided). The comparison to hGRα is not supported: the Abstract says hGRα affects transcription after ligand binding. (LLM, conf=0.88)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“Pharmacologic inhibition of JNK signaling significantly increased DEX-induced GR-GRE binding, as well as DEX-induced reporter gene activity in mouse L929 fibroblasts and mouse hippocampal HT22 cells.”
§ Cytokines and Glucocorticoid Receptor Signaling > Cytokine Effects on GR Function
What the sources say
- Could not verifycites [48] Biola A 2001 Interleukin-2 inhibits glucocorticoid receptor transcriptional activity through a mechanism involving STAT5 (signal transducer and activator of transcription 5) but not AP-1 Mol Endocrinol 15 1062 1076 11435608 sourceExperimental — accuracy not yet measured
The Fig. 1 passage describes IL-2 effects on DEX-induced GR activity in CTLL-2 cells, and the DNA-binding methods describe recombinant rat GR. Searches for JNK inhibition, L929 cells, and HT22 cells found no passage addressing the claimed effect; the cited experiments do not establish it. (LLM, conf=0.76)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Could not verify
Every source the paper cites for this claim was checked and supports it.
In the paper
“Treatment of human lung fibroblasts and vascular smooth muscle cells with the β2 adrenergic receptor agonists, salbutamol or salmeterol, was found to initiate GR translocation from cytoplasm to nucleus, increase GR-DNA binding, and increase GR-mediated gene transcription.111”
§ Cytokines and Glucocorticoid Receptor Signaling > Treatment Implications > PKA
What the sources say
- Supportedcites [111] Eickelberg O 1999 Ligand-independent activation of the glucocorticoid receptor by beta2-adrenergic receptor agonists in primary human lung fibroblasts and vascular smooth muscle cells J Biol Chem 274 1005 1010 9873044 source
Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“In the same study, addition of cAMP alone was also shown to induce GR-GRE binding and a PKA-inhibiting peptide reduced this effect.”
§ Cytokines and Glucocorticoid Receptor Signaling > Treatment Implications > PKA
What the sources say
- Partly supportedcites [111] Eickelberg O 1999 Ligand-independent activation of the glucocorticoid receptor by beta2-adrenergic receptor agonists in primary human lung fibroblasts and vascular smooth muscle cells J Biol Chem 274 1005 1010 9873044 sourceExperimental — accuracy not yet measured
The Results (p. 4) report that two cAMP mimetics induced GR–GRE binding. But the PKA-inhibiting peptide was tested against salmeterol-induced GR activation, not cAMP-induced binding, so the source does not establish that it reduced the effect of cAMP alone. (LLM, conf=0.90)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Chronic caregivers also exhibited significant increases in peripheral blood IL-1ra, as well as increases in CRP, the mean of which was in the high-risk (high-inflammation) category for cardiovascular disease established by the Centers for Disease Control and Prevention and the American Heart Association (>3 mg/L).90”
§ Cytokines and Glucocorticoid Receptor Signaling > Relationship between Inflammation and GR Signaling in Major Depression and Stress
What the sources say
- Supportedcites [89] Miller G 2008 A functional genomic finger-print of chronic stress in humans: Blunted glucocorticoid and increased NF-kappaB signaling Biol Psychiatry 64 4 266 272 18440494 PMC2581622 source
Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
- Not checked — no full text of the sourcecites [90] Pearson T 2003 Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association Circulation 107 499 511 12551878 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Compared to controls, peripheral blood monocytes isolated from subjects exposed to chronic caregiving stress exhibited significant increases in expression of genes containing promoter response elements for NF-κB and significant decreases in genes containing promoter elements for the GR (Fig. 3).”
§ Cytokines and Glucocorticoid Receptor Signaling > Relationship between Inflammation and GR Signaling in Major Depression and Stress
What the sources say
- Supportedcites [89] Miller G 2008 A functional genomic finger-print of chronic stress in humans: Blunted glucocorticoid and increased NF-kappaB signaling Biol Psychiatry 64 4 266 272 18440494 PMC2581622 source
Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Altered GR function in depression has been demonstrated by neuroendocrine challenge tests that reliably reveal reduced GR sensitivity as manifested by nonsuppression of cortisol following dexamethasone administration in vivo and lack of immune suppression following administration of glucocorticoids in vitro.”
§ Cytokines and Glucocorticoid Receptor Signaling > Abstract
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: unclear — It is unclear why the paper says it holds.
It may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“major depression is a disorder that is characterized by hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis and increased release of glucocorticoids”
§ Cytokines and Glucocorticoid Receptor Signaling > Introduction
What the sources say
- Not checked — no full text of the sourcecites [7] Pariante C Miller A 2001 Glucocorticoid receptors in major depression: relevance to pathophysiology and treatment Biol Psychiatry 49 391 404 11274650 source
- Not checked — no full text of the sourcecites [8] Holsboer F 2000 The corticosteroid receptor hypothesis of depression Neuropsychopharmacology 23 477 501 11027914 source
- Not checked — no full text of the sourcecites [9] Rhen T Cidlowski J 2005 Antiinflammatory action of glucocorticoids—new mechanisms for old drugs N Engl J Med 353 1711 1723 16236742 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“One of the more reproducible findings in biological psychiatry is increased activation of the HPA axis and elevated circulating concentrations of the glucocorticoid cortisol in patients with major depression.7,8,10”
§ Cytokines and Glucocorticoid Receptor Signaling > Glucocorticoid Resistance in Major Depression
What the sources say
- Not checked — no full text of the sourcecites [7] Pariante C Miller A 2001 Glucocorticoid receptors in major depression: relevance to pathophysiology and treatment Biol Psychiatry 49 391 404 11274650 source
- Not checked — no full text of the sourcecites [8] Holsboer F 2000 The corticosteroid receptor hypothesis of depression Neuropsychopharmacology 23 477 501 11027914 source
- Not checked — no full text of the sourcecites [10] Raison C Miller A 2003 When not enough is too much: the role of insufficient glucocorticoid signaling in the pathophysiology of stress-related disorders Am J Psychiatry 160 1554 1565 12944327 source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“A number of studies have found evidence of increased CRF activity in patients with major depression, including increased CSF concentrations of CRF and increased CRF mRNA and protein in the hypothalamus of postmortem brain samples from depressed patients.7,10,32”
§ Cytokines and Glucocorticoid Receptor Signaling > Inflammation and Major Depression
What the sources say
- Not checked — no full text of the sourcecites [7] Pariante C Miller A 2001 Glucocorticoid receptors in major depression: relevance to pathophysiology and treatment Biol Psychiatry 49 391 404 11274650 source
- Not checked — no full text of the sourcecites [10] Raison C Miller A 2003 When not enough is too much: the role of insufficient glucocorticoid signaling in the pathophysiology of stress-related disorders Am J Psychiatry 160 1554 1565 12944327 source
- Not checked yetcites [32] Owens M Nemeroff C 1993 The role of corticotropin-releasing factor in the pathophysiology of affective and anxiety disorders: laboratory and clinical studies Ciba Found Symp 172 296 308 discussion 308–316 8491091
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“One possibility is that although circulating concentrations of glucocorticoids may be high (or normal), signaling through the GR may be low.10”
§ Cytokines and Glucocorticoid Receptor Signaling > Glucocorticoid Resistance in Major Depression
What the sources say
- Not checked — no full text of the sourcecites [10] Raison C Miller A 2003 When not enough is too much: the role of insufficient glucocorticoid signaling in the pathophysiology of stress-related disorders Am J Psychiatry 160 1554 1565 12944327 source
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“as has activation of protein kinase A (PKA)”
§ Cytokines and Glucocorticoid Receptor Signaling > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“both the DST and the DEX-CRF test have been shown to predict clinical response to antidepressants”
§ Cytokines and Glucocorticoid Receptor Signaling > Glucocorticoid Resistance in Major Depression
What the sources say
- Not checked — no full text of the sourcecites [10] Raison C Miller A 2003 When not enough is too much: the role of insufficient glucocorticoid signaling in the pathophysiology of stress-related disorders Am J Psychiatry 160 1554 1565 12944327 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“hGR-α contains the full set of 12 α helices required for ligand binding, while hGR-β is unable to bind cortisol due a modified 11th and absent 12th alpha helix.”
§ Cytokines and Glucocorticoid Receptor Signaling > Cytokine Effects on GR Function
What the sources say
- Not checked — no full text of the sourcecites [74] Lewis-Tuffin L Cidlowski J 2006 The physiology of human glucocorticoid receptor beta (hGR-beta) and glucocorticoid resistance Ann N Y Acad Sci 1069 1 9 16855130 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“these observations are somewhat confounded because nimesulide also inhibits phosphodiesterase (PDE) type IV, and PDE IV inhibitors, like rolipram, have been shown to enhance GR function (see below).70,71”
§ Cytokines and Glucocorticoid Receptor Signaling > Cytokine Effects on GR Function
What the sources say
- Not checked — no full text of the sourcecites [70] Bevilacqua M 1994 Nimesulide decreases superoxide production by inhibiting phosphodiesterase type IV Eur J Pharmacol 268 415 423 7805766 source
- Not checked — no full text of the sourcecites [71] Miller A Vogt G Pearce B 2002 The phosphodiesterase type 4 inhibitor, rolipram, enhances glucocorticoid receptor function Neuropsychopharmacology 27 939 948 12464451 source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“following stressor administration, depressed patients became significantly less sensitive to DEX in vitro, whereas controls became significantly more sensitive.87”
§ Cytokines and Glucocorticoid Receptor Signaling > Relationship between Inflammation and GR Signaling in Major Depression and Stress
What the sources say
- Not checked — no full text of the sourcecites [87] Miller G 2005 Clinical depression and regulation of the inflammatory response during acute stress Psychosom Med 67 679 687 16204423 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Activation of JNK results in phosphorylation of c-Jun, which in turn dimerizes with c-Fos to form AP-1, which has been shown to interact with the GR through protein-protein interactions (Fig. 2).62”
§ Cytokines and Glucocorticoid Receptor Signaling > Cytokine Effects on GR Function
What the sources say
- Not checked — no full text of the sourcecites [62] Smoak K Cidlowski J 2004 Mechanisms of glucocorticoid receptor signaling during inflammation Mech Ageing Dev 125 697 706 15541765 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Taken together, these data provide powerful confirmatory evidence that stress (a common precipitant of neuropsychiatric disorders, including depression) can lead to reduced GR function that is characterized by alterations in GR translocation and is mediated by stress-induced innate immune cytokines, such as IL-1.”
§ Cytokines and Glucocorticoid Receptor Signaling > Cytokine Effects on GR Function
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Given the coexistence of glucocorticoid resistance and increased inflammation in patients with major depression, there has been speculation that cytokine effects on the GR may be an important link in this association.”
§ Cytokines and Glucocorticoid Receptor Signaling > Cytokine Effects on GR Function
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
In the paper
“the COX-2 inhibitor nimesulide has been shown to induce GR-DNA binding, GR-mediated gene transcription and GR phosphorylation in cultured human osteoarthritic synovial fibroblast cells.69”
§ Cytokines and Glucocorticoid Receptor Signaling > Cytokine Effects on GR Function
What the sources say
- Not checked — no full text of the sourcecites [69] Di Battista J 1999 Enhancement of phosphorylation and transcriptional activity of the glucocorticoid receptor in human synovial fibroblasts by nimesulide, a preferential cyclooxygenase 2 inhibitor Arthritis Rheum 42 157 166 9920026 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“innate immune cytokines, including TNF-α, are capable of influencing activity of the p-glycoprotein (multidrug resistance) pump, which pumps the glucocorticoids, cortisol and DEX, out of the cell, while having no effect on corticosterone or RU38486.83”
§ Cytokines and Glucocorticoid Receptor Signaling > Cytokine Effects on GR Function
What the sources say
- Not checked — no full text of the sourcecites [83] Pariante C 2008 The role of multi-drug resistance p-glycoprotein in glucocorticoid function: studies in animals and relevance in humans Eur J Pharmacol 583 263 271 18275949 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“One report found that while expression of hGR-α is decreased in patients with major depression, -β expression is unchanged.76”
§ Cytokines and Glucocorticoid Receptor Signaling > Cytokine Effects on GR Function
What the sources say
- Not checked — no full text of the sourcecites [76] Matsubara T 2006 Reduced glucocorticoid receptor alpha expression in mood disorder patients and first-degree relatives Biol Psychiatry 59 689 695 16458268 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Chronic, low dose TNF-α has been found to increase the expression and activity of the p-glycoprotein pump, while higher doses and acute administration of this cytokine-inhibited pump activity.84”
§ Cytokines and Glucocorticoid Receptor Signaling > Cytokine Effects on GR Function
What the sources say
- Not checked — no full text of the sourcecites [84] Bauer B Hartz A Miller D 2007 Tumor necrosis factor alpha and endothelin-1 increase P-glycoprotein expression and transport activity at the blood-brain barrier Mol Pharmacol 71 667 675 17132686 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“One possibility is that IL-1–induced decreases in GR shuttling from cytoplasm to nucleus may lead to reduced autoregulation of receptor expression and thus a compensatory GR upregulation.”
§ Cytokines and Glucocorticoid Receptor Signaling > Cytokine Effects on GR Function
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Indeed, NF-κB–mediated repression of GR activity is inhibited by overexpression of CBP (and vice versa), and GR activity is also inhibited by SRC-1 over-expression.68”
§ Cytokines and Glucocorticoid Receptor Signaling > Cytokine Effects on GR Function
What the sources say
- Not checked — no full text of the sourcecites [68] Sheppard K 1998 Nuclear integration of glucocorticoid receptor and nuclear factor-kappaB signaling by CREB-binding protein and steroid receptor coactivator-1 J Biol Chem 273 29291 29294 9792627 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“another study found that cytokine levels in depressed patients with evidence of glucocorticoid resistance and glucocorticoid excess were low, suggesting that glucocorticoid sensitivity in depressed subjects is maintained or possibly increased during depressive illness.86”
§ Cytokines and Glucocorticoid Receptor Signaling > Relationship between Inflammation and GR Signaling in Major Depression and Stress
What the sources say
- Not checked — no full text of the sourcecites [86] Schuld A 2003 Hypothalamo-pituitary-adrenal function in patients with depressive disorders is correlated with baseline cytokine levels, but not with cytokine responses to hydrocortisone J Psychiatr Res 37 463 470 14563377 source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Standard antidepressants appear to possess some of this dual mechanism of action, as do drugs that target protein kinase A (PKA) signaling pathways.”
§ Cytokines and Glucocorticoid Receptor Signaling > Treatment Implications
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.
In the paper
“The GR antagonist RU486 blocks this effect, demonstrating its dependence on the GR.”
§ Cytokines and Glucocorticoid Receptor Signaling > Treatment Implications > PKA
What the sources say
- Not checked — no full text of the sourcecites [112] Medh R 1998 Resistance of human leukemic CEM-C1 cells is overcome by synergism between glucocorticoid and protein kinase A pathways: correlation with c-Myc suppression Cancer Res 58 3684 3693 9721879
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“the transformational state of GR and phosphorylation of GR by PKA can be inhibited by H-8, a PKA inhibitor.108”
§ Cytokines and Glucocorticoid Receptor Signaling > Treatment Implications > PKA
What the sources say
- Not checked — no full text of the sourcecites [108] Haske T Nakao M Moudgil V 1994 Phosphorylation of immunopurified rat liver glucocorticoid receptor by the catalytic subunit of cAMP-dependent protein kinase Mol Cell Biochem 132 163 171 7969099 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“PKA agonists, including forskolin and 8-Br-cAMP, increase GR mRNA stability and GR mRNA levels and enhance GR transcription and function.109,110”
§ Cytokines and Glucocorticoid Receptor Signaling > Treatment Implications > PKA
What the sources say
- Not checked — no full text of the sourcecites [109] Penuelas I 1998 cAMP activates transcription of the human glucocorticoid receptor gene promoter J Steroid Biochem Mol Biol 67 89 94 9877208 source
- Not checked — no full text of the sourcecites [110] Dong Y 1989 The mechanism of cAMP-induced glucocorticoid receptor expression. Correlation to cellular glucocorticoid response J Biol Chem 264 13679 13683 2547771 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Moreover, flattening of the cortisol curve has been associated with fatigue in breast cancer survivors.101”
§ Cytokines and Glucocorticoid Receptor Signaling > IFN-α as a Model System to Study HPA-Immune Interactions in Depression
What the sources say
- Not checked — no full text of the sourcecites [101] Bower J 2005 Diurnal cortisol rhythm and fatigue in breast cancer survivors Psychoneuroendocrinology 30 92 100 15358446 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“in a study examining symptom criteria for major depression, 45% of patients receiving high dose IFN-α for cancer treatment met criteria for major depression and a third of patients dropped out of IFN-α treatment due to behavioral toxicity.98”
§ Cytokines and Glucocorticoid Receptor Signaling > IFN-α as a Model System to Study HPA-Immune Interactions in Depression
What the sources say
- Not checked — no full text of the sourcecites [98] Musselman D 2001 Paroxetine for the prevention of depression induced by high-dose interferon alfa N Engl J Med 344 961 966 11274622 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“These data were interpreted to suggest that exaggerated HPA axis responses to the first injection of IFN-α in patients who developed depression during IFN-α therapy were likely secondary to sensitized neuroendocrine responses, possibly as a function of sensitized CRF pathways, which in turn represent a vulnerability to IFN-α–induced behavioral change.”
§ Cytokines and Glucocorticoid Receptor Signaling > IFN-α as a Model System to Study HPA-Immune Interactions in Depression
What the sources say
- Not checked — no full text of the sourcecites [96] Capuron L 2003 Association of exaggerated HPA axis response to the initial injection of interferon-alpha with development of depression during interferon-alpha therapy Am J Psychiatry 160 1342 1345 12832253 source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These studies suggest that COX-2 inhibitors may serve to enhance GR function and potentially reverse glucocorticoid resistance through inhibition of p38 and/or JNK.”
§ Cytokines and Glucocorticoid Receptor Signaling > Treatment Implications > COX-2 Inhibitors
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Anisomycin activates both p38 and JNK signaling pathways.
In the paper
“Although DEX (up to 1 uM) fails to cause cell death in glucocorticoid-resistant lymphoid cells (CEM-C1), when combined with forskolin DEX (1 uM) causes 90% cell death.112”
§ Cytokines and Glucocorticoid Receptor Signaling > Treatment Implications > PKA
What the sources say
- Not checked — no full text of the sourcecites [112] Medh R 1998 Resistance of human leukemic CEM-C1 cells is overcome by synergism between glucocorticoid and protein kinase A pathways: correlation with c-Myc suppression Cancer Res 58 3684 3693 9721879
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Prominent symptoms include depressed mood, anhedonia, fatigue, psychomotor slowing, anxiety, and insomnia.97”
§ Cytokines and Glucocorticoid Receptor Signaling > IFN-α as a Model System to Study HPA-Immune Interactions in Depression
What the sources say
- Not checked — no full text of the sourcecites [97] Capuron L 2002 Neurobehavioral effects of interferon-alpha in cancer patients: phenomenology and paroxetine responsiveness of symptom dimensions Neuropsychopharmacology 26 643 652 11927189 source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“Flattening of the cortisol curve has been reported in a number of medical conditions, including cardiovascular disease and cancer, and has been associated with a worse outcome in these disorders.99,100”
§ Cytokines and Glucocorticoid Receptor Signaling > IFN-α as a Model System to Study HPA-Immune Interactions in Depression
What the sources say
- Not checked — no full text of the sourcecites [99] Sephton S 2000 Diurnal cortisol rhythm as a predictor of breast cancer survival J Natl Cancer Inst 92 994 1000 10861311 source
- Not checked — no full text of the sourcecites [100] Matthews K 2006 Diurnal cortisol decline is related to coronary calcification: CARDIA study Psychosom Med 68 657 661 17012518 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“IFN-α has been shown, like other innate immune cytokines, to stimulate the release of CRF in the rat hypothalamus and amygdala and increase the release of CRF protein from rat hypothalamic explants.94,95”
§ Cytokines and Glucocorticoid Receptor Signaling > IFN-α as a Model System to Study HPA-Immune Interactions in Depression
What the sources say
- Not checked — no full text of the sourcecites [94] Raber J Koob G Bloom F 1997 Interferon-alpha and transforming growth factor-beta 1 regulate corticotropin-releasing factor release from the amygdala: comparison with the hypothalamic response Neurochem Int 30 455 463 9106261 source
- Not checked yetcites [95] Gisslinger H 1993 Interferon-alpha stimulates the hypothalamic-pituitary-adrenal axis in vivo and in vitro Neuroendocrinology 57 489 495 8391662
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“IFN-α has both antiviral and antiproliferative properties and, therefore, is used clinically for the treatment of infectious diseases and cancers, including malignant melanoma and renal cell carcinoma.91”
§ Cytokines and Glucocorticoid Receptor Signaling > IFN-α as a Model System to Study HPA-Immune Interactions in Depression
What the sources say
- Not checked — no full text of the sourcecites [91] Raison C 2005 Neuropsychiatric adverse effects of interferon-alpha: recognition and management CNS Drugs 19 105 123 15697325 PMC1255968 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“Early studies revealed that the antidepressant desipramine is capable of increasing both DEX-induced GR-mediated gene transcription and GR translocation (even in the absence of DEX).102”
§ Cytokines and Glucocorticoid Receptor Signaling > Treatment Implications > Antidepressants
What the sources say
- Not checked — no full text of the sourcecites [102] Pariante C 1997 Steroid-independent translocation of the glucocorticoid receptor by the antidepressant desipramine Mol Pharmacol 52 571 581 9380019 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“there is evidence of both glucocorticoid resistance and increased inflammatory markers, including elevated innate immune cytokines, in patients with major depression.”
§ Cytokines and Glucocorticoid Receptor Signaling > Summary
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper relies on this without support.
Cyclic AMP/PKA signal transduction pathways are reduced in postmortem brain tissue from depressed patients.
“Cyclic AMP/PKA signal transduction pathways have also been shown to be reduced in postmortem brain tissue from depressed patients.”
The paper relies on this without support.
IFN-α activates Jak-STAT and p38 MAPK signaling pathways.
“IFN-α is well known to activate Jak-STAT as well as p38 MAPK signaling pathways”
The paper relies on this without support.
Anisomycin activates both p38 and JNK signaling pathways.
“Anisomycin activates both p38 and JNK signaling pathways.”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Cytokines and Glucocorticoid Receptor Signaling > Cytokine Effects on GR Function
“which inactivates cortisol”
§ Cytokines and Glucocorticoid Receptor Signaling > Cytokine Effects on GR Function
“thereby increasing the availability of glucocorticoids.”
Citations
Cites
From inflammation to sickness and depression: when the immune system subjugates the brain
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Pearson, T. A., Mensah, G. A., Alexander, R. W., Anderson, J. L., Cannon, R. O., Criqui, M., Fadl, Y. Y., Fortmann, S. P., Hong, Y., Myers, G. L., et al. (2003) · Circulation · doi:10.1161/01.cir.0000052939.59093.45 · Cited by 6,401
Antiinflammatory Action of Glucocorticoids — New Mechanisms for Old Drugs
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Cytokines sing the blues: inflammation and the pathogenesis of depression
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Self-citationBrain corticosteroid receptor balance in health and disease
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Brain corticosteroid receptor balance in health and disease
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Clinical application of C-reactive protein for cardiovascular disease detection and prevention
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The Corticosteroid Receptor Hypothesis of Depression
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Immune-neuro-endocrine interactions: facts and hypotheses.
BESEDOVSKY, H. O., & REY, A. D. (1996) · Endocrine Reviews · doi:10.1210/edrv-17-1-64 · Cited by 1,564
Inflammation and cancer: how hot is the link?
Aggarwal, B. B., Shishodia, S., Sandur, S. K., Pandey, M. K., & Sethi, G. (2006) · Biochemical Pharmacology · doi:10.1016/j.bcp.2006.06.029 · Cited by 1,312
Cited by
Sorted by citations
Slavich, G. M., & Irwin, M. R. (2014) · Psychological Bulletin · doi:10.1037/a0035302 · Cited by 2,206
“To our knowledge, however, no studies to date have tested for differences in the leukocyte basal transcriptome of depressed versus nondepressed individuals (for related work, see S. W. Cole, 2009, 2010; Fredrickson et al., 2013; A. H. Miller et al., 2009; Pace & Miller, 2009).”
BackgroundGoldsmith, D. R., Rapaport, M. H., & Miller, B. J. (2016) · Molecular Psychiatry · doi:10.1038/mp.2016.3 · Cited by 1,683
Effects of stress on immune function: The good, the bad, and the beautiful
Dhabhar, F. S. (2014) · Immunologic Research · doi:10.1007/s12026-014-8517-0 · Cited by 1,343
Immune system to brain signaling: Neuropsychopharmacological implications
Capuron, L., & Miller, A. H. (2011) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2011.01.014 · Cited by 1,195
“One mechanism by which chronic cytokine exposure may influence HPA axis function is through inhibitory effects on the receptor for the glucocorticoid, cortisol, the end product of HPA axis activation (Pace and Miller, 2009).”
BackgroundSelf-citationDepression and obesity: evidence of shared biological mechanisms
Milaneschi, Y., Simmons, W. K., van Rossum, E. F. C., & Penninx, B. W. (2019) · Molecular Psychiatry · doi:10.1038/s41380-018-0017-5 · Cited by 1,073
Metadata
- Authors
- Pace, T. W. W., & Miller, A. H.
- Affiliations
- Emory University (US)
- Corresponding author
- Miller, Andrew H.
- Venue
- Annals of the New York Academy of Sciences
- Publisher
- Wiley
- Published
- 2009-10
- Volume
- 1179
- Issue
- 1
- Pages
- 86-105
- ISSN
- 0077-8923 (ISSN-L)
- 1749-6632
- PMC
- PMC3399249
- OpenAlex
- W2066044455
- Semantic Scholar
- 687f86caf558ed684a6c4ad389bb1ba1e1f87c02
- Cited by
- 339
- References
- 126
- Citations by year
- 2026: 11 · 2025: 12 · 2024: 21 · 2023: 13 · 2022: 15 · 2021: 43 · 2020: 13 · 2019: 14 · 2018: 15 · 2017: 25 · 2016: 27 · 2015: 21 · 2014: 23 · 2013: 24 · 2012: 26
- FWCI
- 1.11
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Annals of the New York Academy of Sciences (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL073921)
- National Institute of Mental Health (R03MH079870, R01MH075102, K05MH069124)
- National Center for Research Resources (M01-RR00039, UL1RR025008, M01RR000039)
- National Center for Advancing Translational Sciences (UL1 TR000454)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Keywords
- major depressive disorder, glucocorticoid receptor, inflammatory cytokines, glucocorticoid resistance, dexamethasone suppression test, p38 MAPK, STAT5, NF-κB, protein kinase A, antidepressants, neuroendocrine challenge
- MeSH terms
- Cross-Sectional Studies, Major Depressive Disorder, Depressive Disorder, Major, Glucocorticoids, Humans, Inflammation, Models, Biological, Receptors, Glucocorticoid, Signal Transduction, Cytokines, NF-kappa B, p38 Mitogen-Activated Protein Kinases
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-28, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-28 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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