Activation of cAMP-protein kinase A abrogates STAT5-mediated inhibition of glucocorticoid receptor signaling by interferon-alpha

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

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

IFN-alpha has been found to inhibit glucocorticoid receptor (GR) function by activating janus kinase-signal transducer and activator of transcription (JAK-STAT) inflammatory signaling pathways. In contrast, through stimulation of protein kinase A (PKA), cAMP has been shown to enhance GR function and can inhibit inflammatory signaling. We therefore examined whether increased cAMP-PKA pathway activation could reverse IFN-alpha-induced inhibition of GR function and whether decreased cAMP-PKA activity might exacerbate IFN-alpha effects on the GR. Activation of cAMP by forskolin (10 μM) reversed the inhibitory effects of mIFN-alpha (1000. U/ml) on dexamethasone (DEX)-induced MMTV-luciferase activity in hippocampal HT22 cells. Forskolin treatment also blocked both IFN-alpha-induced activation of phosphorylated STAT5 (pSTAT5) and inhibitory protein-protein interactions between pSTAT5 and GR in the nucleus of HT22 cells treated with IFN-alpha and DEX. These effects of forskolin were reversed by co-administration of the PKA inhibitor, H89. Conversely, the combination of IFN-alpha and treatment with either H89 or siRNA directed against the alpha and beta catalytic subunit isoforms of PKA led to an additive inhibitory effect on DEX-induced GR activity in HT22 cells. Taken together, these findings suggest that inhibition of GR signaling by mIFN-alpha and STAT5 can be reversed by activation of cAMP-PKA pathways, whereas decreased PKA activity increases the inhibitory effect of IFN-alpha on GR function. Given decreased PKA activity found in patients with major depression, these data suggest that depressed patients may be vulnerable to cytokine effects on GR, and cAMP-PKA agonists may serve to reverse glucocorticoid resistance in patients with depression and increased inflammation.

Original languageEnglish (US)
Pages (from-to)1716-1724
Number of pages9
JournalBrain, Behavior, and Immunity
Volume25
Issue number8
DOIs
StatePublished - Nov 2011
Externally publishedYes

Keywords

  • Beta-adrenergic receptor
  • Cytokine
  • Glucocorticoid receptor
  • Interferon-alpha
  • JAK-STAT
  • Major depression
  • PKA
  • STAT5

ASJC Scopus subject areas

  • Immunology
  • Endocrine and Autonomic Systems
  • Behavioral Neuroscience

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