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Cited by 339Stress Responses and CortisolTryptophan and brain disordersTreatment of Major Depression

Cytokines and Glucocorticoid Receptor Signaling

Open access
Pace, Thaddeus W. W., Miller, Andrew H.·2009·Annals of the New York Academy of Sciences
DOI 10.1111/j.1749-6632.2009.04984.xPMC PMC3399249
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Abstract

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.

AI snapshot

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.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1111/j.1749-6632.2009.04984.x

Cites

127 of 127 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

43 of 164 cited sources checked · 20 supported · 0 flagged · accuracy not yet measured

  • Interpretationcitation

    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.

    “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”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [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
  • Interpretationcitation

    These effects of innate immune cytokines on glucocorticoid receptors (GRs) may represent a contributing pathophysiologic pathway to the development of major depression.

    “These effects of innate immune cytokines on glucocorticoid receptors (GRs) may represent a contributing pathophysiologic pathway to the development of major depression”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [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
  • Interpretationcitation

    Cytokines can influence virtually every pathophysiologic pathway relevant to depression, including neurotransmitter metabolism, neuroendocrine function, synaptic plasticity and regional brain activity.

    “data indicate that cytokines can influence virtually every pathophysiologic pathway relevant to depression, including neurotransmitter metabolism, neuroendocrine function, synaptic plasticity and regional brain activity.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [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

      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)

      Experimental — accuracy not yet measured
  • Premisecitation

    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.

    “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”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [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
    • cites [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
    • cites [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
  • Premisecitation

    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.

    “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”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [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
    • cites [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

      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)

      Experimental — accuracy not yet measured
  • May combine two claims. 36
  • Classified as probably not a substantial claim. 8

  • May combine two claims.

    Premisecitation

    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).

    “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)”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [79] Lewis-Tuffin L 2007 Human glucocorticoid receptor beta binds RU-486 and is transcriptionally active Mol Cell Biol 27 2266 2282 17242213 PMC1820503 source

      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)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    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.

    “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.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [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 source

      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)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Treatment of human lung fibroblasts and vascular smooth muscle cells with β2 adrenergic receptor agonists salbutamol or salmeterol initiates GR translocation from cytoplasm to nucleus, increases GR-DNA binding, and increases GR-mediated gene transcription.

    “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”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [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

  • May combine two claims.

    Premisecitation

    In the same study, addition of cAMP alone induced GR-GRE binding and a PKA-inhibiting peptide reduced this effect.

    “In the same study, addition of cAMP alone was also shown to induce GR-GRE binding and a PKA-inhibiting peptide reduced this effect.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [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

      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)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    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).

    “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”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [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
    • cites [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

  • May combine two claims.

    Premisecitation

    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.

    “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).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [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

  • May combine two claims.

    Premisenone given

    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.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Major depression is characterized by hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis and increased release of glucocorticoids.

    “major depression is a disorder that is characterized by hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis and increased release of glucocorticoids”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [7] Pariante C Miller A 2001 Glucocorticoid receptors in major depression: relevance to pathophysiology and treatment Biol Psychiatry 49 391 404 11274650 source
    • cites [8] Holsboer F 2000 The corticosteroid receptor hypothesis of depression Neuropsychopharmacology 23 477 501 11027914 source
    • cites [9] Rhen T Cidlowski J 2005 Antiinflammatory action of glucocorticoids—new mechanisms for old drugs N Engl J Med 353 1711 1723 16236742 source

  • May combine two claims.

    Premisecitation

    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.

    “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”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [7] Pariante C Miller A 2001 Glucocorticoid receptors in major depression: relevance to pathophysiology and treatment Biol Psychiatry 49 391 404 11274650 source
    • cites [8] Holsboer F 2000 The corticosteroid receptor hypothesis of depression Neuropsychopharmacology 23 477 501 11027914 source
    • cites [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

  • May combine two claims.

    Premisecitation

    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.

    “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”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [7] Pariante C Miller A 2001 Glucocorticoid receptors in major depression: relevance to pathophysiology and treatment Biol Psychiatry 49 391 404 11274650 source
    • cites [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
    • cites [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

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationcitation

    Although circulating concentrations of glucocorticoids may be high (or normal), signaling through the GR may be low.

    “One possibility is that although circulating concentrations of glucocorticoids may be high (or normal), signaling through the GR may be low.10”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Activation of protein kinase A (PKA) enhances GR function.

    “as has activation of protein kinase A (PKA)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Both the DST and the DEX-CRF test have been shown to predict clinical response to antidepressants.

    “both the DST and the DEX-CRF test have been shown to predict clinical response to antidepressants”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

  • May combine two claims.

    Premisecitation

    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.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

  • May combine two claims.

    Premisecitation

    These observations are confounded because nimesulide also inhibits phosphodiesterase (PDE) type IV, and PDE IV inhibitors, like rolipram, have been shown to enhance GR function.

    “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”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [70] Bevilacqua M 1994 Nimesulide decreases superoxide production by inhibiting phosphodiesterase type IV Eur J Pharmacol 268 415 423 7805766 source
    • cites [71] Miller A Vogt G Pearce B 2002 The phosphodiesterase type 4 inhibitor, rolipram, enhances glucocorticoid receptor function Neuropsychopharmacology 27 939 948 12464451 source

  • May combine two claims.

    Premisecitation

    Following stressor administration, depressed patients became significantly less sensitive to DEX in vitro, whereas controls became significantly more sensitive.

    “following stressor administration, depressed patients became significantly less sensitive to DEX in vitro, whereas controls became significantly more sensitive.87”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [87] Miller G 2005 Clinical depression and regulation of the inflammatory response during acute stress Psychosom Med 67 679 687 16204423 source

  • May combine two claims.

    Premisecitation

    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.

    “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”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [62] Smoak K Cidlowski J 2004 Mechanisms of glucocorticoid receptor signaling during inflammation Mech Ageing Dev 125 697 706 15541765 source

  • May combine two claims.

    Interpretationreasoning

    These data provide powerful confirmatory evidence that stress 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.

    “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.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationreasoning

    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.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The COX-2 inhibitor nimesulide induces GR-DNA binding, GR-mediated gene transcription and GR phosphorylation in cultured human osteoarthritic synovial fibroblast cells.

    “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”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

  • May combine two claims.

    Premisecitation

    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.

    “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”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

  • May combine two claims.

    Premisecitation

    One report found that while expression of hGR-α is decreased in patients with major depression, hGR-β expression is unchanged.

    “One report found that while expression of hGR-α is decreased in patients with major depression, -β expression is unchanged.76”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [76] Matsubara T 2006 Reduced glucocorticoid receptor alpha expression in mood disorder patients and first-degree relatives Biol Psychiatry 59 689 695 16458268 source

  • May combine two claims.

    Premisecitation

    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.

    “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”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    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.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    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.

    “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”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    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.

    “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”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    Standard antidepressants appear to possess a dual mechanism of action of targeting inflammation and GR function, as do drugs that target PKA signaling pathways.

    “Standard antidepressants appear to possess some of this dual mechanism of action, as do drugs that target protein kinase A (PKA) signaling pathways.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The GR antagonist RU486 blocks the cell death effect of DEX plus forskolin, demonstrating its dependence on the GR.

    “The GR antagonist RU486 blocks this effect, demonstrating its dependence on the GR.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

  • May combine two claims.

    Premisecitation

    The transformational state of GR and phosphorylation of GR by PKA can be inhibited by H-8, a PKA inhibitor.

    “the transformational state of GR and phosphorylation of GR by PKA can be inhibited by H-8, a PKA inhibitor.108”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

  • May combine two claims.

    Premisecitation

    PKA agonists, including forskolin and 8-Br-cAMP, increase GR mRNA stability and GR mRNA levels and enhance GR transcription and function.

    “PKA agonists, including forskolin and 8-Br-cAMP, increase GR mRNA stability and GR mRNA levels and enhance GR transcription and function.109,110”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [109] Penuelas I 1998 cAMP activates transcription of the human glucocorticoid receptor gene promoter J Steroid Biochem Mol Biol 67 89 94 9877208 source
    • cites [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

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Flattening of the cortisol curve has been associated with fatigue in breast cancer survivors.

    “Moreover, flattening of the cortisol curve has been associated with fatigue in breast cancer survivors.101”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [101] Bower J 2005 Diurnal cortisol rhythm and fatigue in breast cancer survivors Psychoneuroendocrinology 30 92 100 15358446 source

  • May combine two claims.

    Premisecitation

    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.

    “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”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

  • May combine two claims.

    Interpretationcitation

    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.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

  • May combine two claims.

    Interpretationreasoning

    COX-2 inhibitors may serve to enhance GR function and potentially reverse glucocorticoid resistance through inhibition of p38 and/or JNK.

    “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.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Anisomycin activates both p38 and JNK signaling pathways.

  • May combine two claims.

    Premisecitation

    In glucocorticoid-resistant lymphoid cells (CEM-C1), DEX up to 1 uM fails to cause cell death, but when combined with forskolin, DEX (1 uM) causes 90% cell death.

    “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”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

  • May combine two claims.

    Premisecitation

    Prominent symptoms include depressed mood, anhedonia, fatigue, psychomotor slowing, anxiety, and insomnia.

    “Prominent symptoms include depressed mood, anhedonia, fatigue, psychomotor slowing, anxiety, and insomnia.97”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

  • May combine two claims.

    Premisecitation

    Flattening of the cortisol curve has been reported in a number of medical conditions, including cardiovascular disease and cancer, and is associated with worse outcome in these disorders.

    “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”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [99] Sephton S 2000 Diurnal cortisol rhythm as a predictor of breast cancer survival J Natl Cancer Inst 92 994 1000 10861311 source
    • cites [100] Matthews K 2006 Diurnal cortisol decline is related to coronary calcification: CARDIA study Psychosom Med 68 657 661 17012518 source

  • May combine two claims.

    Premisecitation

    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.

    “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”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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
    • cites [95] Gisslinger H 1993 Interferon-alpha stimulates the hypothalamic-pituitary-adrenal axis in vivo and in vitro Neuroendocrinology 57 489 495 8391662

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    IFN-α has both antiviral and antiproliferative properties and is used clinically for the treatment of infectious diseases and cancers, including malignant melanoma and renal cell carcinoma.

    “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”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [91] Raison C 2005 Neuropsychiatric adverse effects of interferon-alpha: recognition and management CNS Drugs 19 105 123 15697325 PMC1255968 source

  • May combine two claims.

    Premisecitation

    The antidepressant desipramine increases DEX-induced GR-mediated gene transcription and GR translocation, even in the absence of DEX.

    “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”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [102] Pariante C 1997 Steroid-independent translocation of the glucocorticoid receptor by the antidepressant desipramine Mol Pharmacol 52 571 581 9380019 source

  • May combine two claims.

    Premisenone given

    There is evidence of both glucocorticoid resistance and increased inflammatory markers, including elevated innate immune cytokines, in patients with major depression.

    “there is evidence of both glucocorticoid resistance and increased inflammatory markers, including elevated innate immune cytokines, in patients with major depression.”
    Quote in the paperSubstantial claim
41 of 41

  • 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.”
3 of 3

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.

  • Cortisol inactivation is said to increase glucocorticoid availability

    Minor

    The passage says increased 11β-HSD type 2 activity inactivates cortisol, then says this increases glucocorticoid availability. Inactivating cortisol would not increase the availability of active cortisol.

1 of 1

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Related

Authors
Pace, T. W. W., & Miller, A. H.
Affiliations
Emory University (US)
Corresponding author
Miller, Andrew H.
ORCID
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
DOI
10.1111/j.1749-6632.2009.04984.x
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
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor, 33 d)
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 › 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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-28.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-28.

Cited sources are checked by 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.

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