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.
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- 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.
- 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
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.
- 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
“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
- 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
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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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Immune-neuro-endocrine interactions: facts and hypotheses.
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Inflammation and cancer: how hot is the link?
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Cited by
Sorted by citations
Items 101–200 of 337
Liu, C., Carvalho, A., & McIntyre, R. (2015) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/1871527313666141130204031 · Cited by 61
Claudin-1 expression in airway smooth muscle exacerbates airway remodeling in asthmatic subjects
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Häfner, S., Emeny, R. T., Lacruz, M. E., Baumert, J., Herder, C., Koenig, W., Thorand, B., & Ladwig, K. H. (2011) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2011.06.017 · Cited by 72
“Cytokines have been shown to induce glucocorticoid receptor resistance (Pace et al., 2007; Pace and Miller, 2009).”
BackgroundAllostatic load and mental health: a latent class analysis of physiological dysregulation
Carbone, J. T. (2020) · Stress · doi:10.1080/10253890.2020.1813711 · Cited by 65
“20–80% of individuals experiencing depression have some form of HPA axis hyperactivity and a half to three-quarters of depressed patients have elevated cortisol levels (Pace & Miller, 2009; Stetler and Miller, 2011).”
BackgroundDepression and Metabolic Syndrome: A Narrative Review
Al-Khatib, Y., Akhtar, M. A., Kanawati, M. A., Mucheke, R., Mahfouz, M., & Al-Nufoury, M. (2022) · Cureus · doi:10.7759/cureus.22153 · Cited by 69
“Numerous studies have replicated this finding [74,75,78].”
Glucocorticoids and Inflammation: A Double-Headed Sword in Depression?
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Human social genomics: Concepts, mechanisms, and implications for health
Slavich, G. M., Mengelkoch, S., & Cole, S. W. (2023) · Lifestyle Medicine · doi:10.1002/lim2.75 · Cited by 63
Dedoncker, J., Vanderhasselt, M., Ottaviani, C., & Slavich, G. M. (2021) · Neuroscience and Biobehavioral Reviews · doi:10.1016/j.neubiorev.2021.02.010 · Cited by 49
MicroRNA as therapeutic targets for treatment of depression
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Audet, M. (2010) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2010.00156 · Cited by 57
Energetic stress: The reciprocal relationship between energy availability and the stress response
Harrell, C. S., Gillespie, C. F., & Neigh, G. N. (2015) · Physiology & Behavior · doi:10.1016/j.physbeh.2015.10.009 · Cited by 51
“…whether bacterial or viral challenges or even psychosocial stressors, are known to activate the HPA axis to potentiate hypothalamic secretion of CRF and AVP as well as adrenal glucocorticoid secretion via the actions of cytokines and chemokines (Charmandari et al., 2005, Pace and Miller, 2009).”
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“It was also shown that antidepressants improve the functioning of the glucocorticoid receptor-modulated negative feedback on cortisol levels among human depressed patients (Pariante et al., 2004; Nikisch, 2009; Pace and Miller, 2009; Pariante, 2009).”
BackgroundSex Differences in the Inflammatory Consequences of Stress: Implications for Pharmacotherapy
Martínez-Muñiz, G. A., & Wood, S. K. (2020) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.120.266205 · Cited by 53
“However, patients suffering from depression exhibit significantly higher TSST-induced IL-6 levels than healthy controls (Pace and Miller, 2009).”
BackgroundInflammatory Signaling in Hypertension: Regulation of Adrenal Catecholamine Biosynthesis
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“Therefore, the negative feedback loop, which usually down-regulates cortisol production, is disabled thereby leading to chronic hypercortisolemia(Pace and Miller, 2009; Turnbull and Rivier, 1999).”
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“Constant immune alterations are assumed to contribute to the development of dysregulated behaviors observed in many neurodevelopmental and psychiatric disorders (Pace and Miller, 2009; Borsini et al., 2015).”
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“Chronic psychosocial stress and depression may increase immune activation via greater glucocorticoid resistance (Pace & Miller, 2009; Pace et al., 2006).”
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“Immune alterations are believed to contribute to the behavioral abnormalities associated with many neurodevelopmental and psychiatric disorders (Pace and Miller, 2009).”
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“…feedback cycle can be disrupted in persons exposed to chronic stress due to a decreased sensitivity of the glucocorticoid receptor to chronically elevated cortisol, contributing to overproduction or dysregulated production of pro-inflammatory cytokines (Corwin et al., 2013; Pace & Miller, 2009).”
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“…to the immune system’s adaptive reactions (Steptoe, O’Donnell, Badrick, Kumari, & Marmot, 2007) which trigger many metabolic and behavioural adjustments, such as changes in plasma volume, production of pro-inflammatory cytokines and production of cytokine synthesizing cells (Pace & Miller, 2009).”
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“Proinflammatory cytokines activate elements of the cellular transduction cascades that impede GR nuclear translocation or interfere in GR interactions with response elements in gene promoters (196).”
BackgroundDu, R.-W., Du, R., & Bu, W.-G. (2014) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-014-9556-y · Cited by 33
C57BL/6J bone marrow transplant increases sociability in BTBR T+ Itpr3tf/J mice
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“Persistent immune alterations are thought to contribute to the behavioral sequel associated with many psychiatric and neurodvelopmental disorders (Dantzer, 2006; Pace and Miller, 2009).”
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“Increased levels of cortisol, corticotropin releasing hormone, and the size and activity of pituitary and adrenal glands are often, although not always, found in major depression (Pace and Miller, 2009; Stetler and Miller, 2011; Zunszain et al., 2011).”
BackgroundKim, J. H., Kim, J. Y., Lee, S., Lee, S., Stubbs, B., Koyanagi, A., Dragioti, E., Jacob, L., Carvalho, A. F., Raduà, J., et al. (2022) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2022.104761 · Cited by 36
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“SAM s antiinflammatory action might be important in the treatment of depression, as inflammation might play a role in its initiation and progression [Pace and Miller, 2009].”
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“This is called glucocorticoid resistance [28].”
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“…glucocorticoid receptor mRNA production, increase in the inert glucocorticoid-binding glucocorticoid receptor beta (GR-β ), and disruption of activated glucocorticoid receptor function via translocation blockade and direct protein-protein interactions (Pace and Miller, 2009; Pariante et al., 1999).”
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“The immune dysregulation contributes to the behavioral neurodevelopment and psychiatric disorder (Pace and Miller, 2009).”
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“Administered acutely, cytokines have been shown to increase the expression and the release of CRF, adrenocorticotropic hormone (ACTH), and cortisol (Besedovsky and del Rey, 1996; Pariante and Miller, 2001; Pace and Miller, 2009).”
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“Another consistent finding in the literature is that the level of cortisol hormone is often elevated in depressed individuals, although 30–50% of depressed individuals may not display elevations in cortisol (Muller and Holsboer, 2006; Pace and Miller, 2009).”
BackgroundCao, M., MacDonald, J. W., Liu, H. L., Weaver, M., Cortes, M., Durosier, L. D., Burns, P., Fecteau, G., Desrochers, A., Schulkin, J. A., et al. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01063 · Cited by 20
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“Multiple studies have demonstrated that patients with MDD hypersecrete cortisol (Vreeburg et al., 2009), have impaired glucocorticoid receptor (GR) functioning (Pace & Miller, 2009), and have reduced hippocampal volumes (MacQueen & Frodl, 2011).”
BackgroundObesity and Depression: A Pathophysiotoxic Relationship
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“…cytokines activate elements of the cellular transduction cascades that prevent GR translocation to the nucleus or interfere with the interaction of GRs with response elements that promote gene activation [53], resulting in insensitivity to GC and loss of anti-inflammatory feedback [52].”
Chat, I. K.-Y., Nusslock, R., Moriarity, D. P., Bart, C. P., Giollabhui, N. M., Damme, K. S. F., Carroll, A., Miller, G. E., & Alloy, L. B. (2021) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2021.03.006 · Cited by 19
“…disrupt the autonomic nervous system and the hypothalamic – pituitaryadrenal axis, both of which are involved in regulating peripheral inflammatory signaling (Irwin and Cole, 2011; Miller et al., 2011; Nusslock and Miller, 2016; Pace and Miller, 2009; Raison and Miller, 2003; Rolls et al., 2020).”
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“It is thought that the release of specific inflammatory markers and activation of the immune system may be related to the pathophysiology of depression potentially via the effects of cytokines on specific regions of the brain (Pace and Miller, 2009).”
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“However, proinflammatory cytokines may also interfere with corticosteroids receptors activity, which suggests a more complex balance and feedback [36].”
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“For example, increased HPA axis activity has been recorded in a majority of patients with depression (Pace & Miller, 2009; Stetler & Miller, 2011).”
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“While it is unclear if this results in higher levels of this cytokine in the circulation or the CNS, TNFa can induce NFkB and thereby cause inactivation of GR (Pace and Miller, 2009).”
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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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