Interferon-alpha inhibits glucocorticoid receptor-mediated gene transcription via STAT5 activation in mouse HT22 cells

Fang Hu, Thaddeus W.W. Pace, Andrew H. Miller

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

Interferon (IFN)-alpha is an innate immune cytokine that induces significant depressive symptoms in clinical populations. A number of mechanisms have been considered regarding the relationship between IFN-alpha and depression, including the effects of IFN-alpha on the hypothalamic-pituitary-adrenal (HPA) axis. Here, we examined the impact of mouse interferon (mIFN)-alpha and its signaling pathways on the functioning of the glucocorticoid receptor (GR), which plays a key role in HPA axis regulation. mIFN-alpha treatment (100-1000 IU/ml) of HT22 mouse hippocampal cells for 24 h was found to significantly inhibit dexamethasone (DEX)-induced GR-mediated MMTV-luciferase activity and significantly decrease DEX-induced GR-binding to its DNA response element. Of note, mIFN-alpha treatment for 24 h had no effect on DEX-induced GR translocation or GR protein expression. Inhibition of DEX-induced GR function by mIFN-alpha was significantly reversed by pharmacological inhibition of janus kinase/signal transducer and activator of transcription (Jak-STAT) signaling pathways, but not by inhibition of p38 mitogen-activated protein kinase. Moreover, pretreatment of cells with siRNA targeted to STAT5, but not STAT1 or STAT2, significantly attenuated IFN-alpha inhibition of DEX-induced MMTV-luciferase activity. Immunoprecipitation experiments revealed nuclear co-immunoprecipitation of activated STAT5 and GR following IFN-alpha plus DEX treatment. Taken together, these results indicate that negative regulation of GR function by IFN-alpha in hippocampal HT22 cells is mediated by activation of Jak/STAT signaling pathways leading to nuclear STAT5-GR protein-protein interactions. Given the role of GR in depressive disorders, IFN-alpha effects on GR function in cells of hippocampal origin may contribute to HPA axis alterations and depressive symptoms in IFN-alpha-treated patients.

Original languageEnglish (US)
Pages (from-to)455-463
Number of pages9
JournalBrain, Behavior, and Immunity
Volume23
Issue number4
DOIs
StatePublished - May 1 2009
Externally publishedYes

Keywords

  • Cytokine
  • Glucocorticoid receptor
  • Interferon-alpha
  • Jak-STAT
  • Major depression
  • STAT5

ASJC Scopus subject areas

  • Immunology
  • Endocrine and Autonomic Systems
  • Behavioral Neuroscience

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