Cytokines and glucocorticoid receptor signaling: Relevance to major depression

Thaddeus W.W. Pace, Andrew H. Miller

Research output: Chapter in Book/Report/Conference proceedingConference contribution

205 Scopus citations

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.

Original languageEnglish (US)
Title of host publicationGlucocorticoids and Mood Clinical Manifestations, Risk Factors, and Molecular Mechanisms
PublisherBlackwell Publishing Inc.
Pages86-105
Number of pages20
ISBN (Print)9781573317481
DOIs
StatePublished - 2009

Publication series

NameAnnals of the New York Academy of Sciences
Volume1179
ISSN (Print)0077-8923
ISSN (Electronic)1749-6632

Keywords

  • Cell signaling
  • Cytokines
  • Glucocorticoid
  • Glucocorticoid insensitivity
  • Glucocorticoids
  • Inflammation
  • Mood
  • NF-κB
  • P38 MAPK

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • History and Philosophy of Science

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    Pace, T. W. W., & Miller, A. H. (2009). Cytokines and glucocorticoid receptor signaling: Relevance to major depression. In Glucocorticoids and Mood Clinical Manifestations, Risk Factors, and Molecular Mechanisms (pp. 86-105). (Annals of the New York Academy of Sciences; Vol. 1179). Blackwell Publishing Inc.. https://doi.org/10.1111/j.1749-6632.2009.04984.x