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

• Type of Material: Article
• Authors: Thaddeus Pace, Emory University; Fang Hua, Emory University; Andrew H Miller, Emory University
• Language: English
• Date: 2011-11
• Publisher: Elsevier: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2011 Elsevier Inc. All rights reserved.
• License: Creative Commons Attribution-NonCommerical-NoDerivs 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.1016/j.bbi.2011.07.227
• Title of Journal or Parent Work: Brain, Behavior, and Immunity
• ISSN: 0889-1591
• Volume: 25
• Issue: 8
• Start Page: 1716
• End Page: 1724
• Keywords: cytokine; beta-adrenergic receptor; PKA; STAT5; interferon-alpha; Jak-STAT; major depression; glucocorticoid receptor
• Research Categories: Psychology, General; Biology, Neuroscience

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 (10uM) reversed the inhibitory effects of mIFN-alpha (1000U/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.