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

Brain Behav Immun. 2009 May;23(4):455-63. doi: 10.1016/j.bbi.2009.01.001. Epub 2009 Jan 8.

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 24h 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 24h 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Analysis of Variance
  • Animals
  • Blotting, Western
  • Cell Fractionation
  • Cells, Cultured
  • Dexamethasone / pharmacology
  • Dose-Response Relationship, Drug
  • Electrophoretic Mobility Shift Assay
  • Glucocorticoids / pharmacology
  • Hippocampus / cytology
  • Imidazoles / pharmacology
  • Immunoprecipitation
  • Interferon Type I / metabolism*
  • Interferon Type I / pharmacology*
  • JNK Mitogen-Activated Protein Kinases / genetics
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Mice
  • Mitogen-Activated Protein Kinase 1 / genetics
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Phosphorylation / drug effects
  • Pyridines / pharmacology
  • RNA, Small Interfering / pharmacology
  • Receptors, Glucocorticoid / genetics*
  • Recombinant Proteins
  • Reverse Transcriptase Polymerase Chain Reaction
  • STAT5 Transcription Factor / genetics
  • STAT5 Transcription Factor / metabolism*
  • Subcellular Fractions / metabolism
  • Transcription, Genetic / drug effects*
  • Transfection
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Glucocorticoids
  • Imidazoles
  • Interferon Type I
  • Pyridines
  • RNA, Small Interfering
  • Receptors, Glucocorticoid
  • Recombinant Proteins
  • STAT5 Transcription Factor
  • Dexamethasone
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinase 1
  • p38 Mitogen-Activated Protein Kinases
  • SB 203580