title: Activation of cAMP-protein kinase A abrogates STAT5-mediated inhibition of glucocorticoid receptor signaling by interferon-alpha.
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.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, 1365-B Clifton Rd., Suite 5100, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA. thaddeus.pace@emory.edu
authors.forename: Thaddeus W W
authors.initials: TW
authors.lastname: Pace
authors.forename: Fang
authors.initials: F
authors.lastname: Hu
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Miller
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D004789:Enzyme Activation / Q000502:physiology; D047468:Immunoprecipitation; D007202:Indicators and Reagents; D016898:Interferon-alpha / Q000494:pharmacology*; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation; D050828:Protein Inhibitors of Activated STAT / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors* / Q000502:physiology; D050799:STAT5 Transcription Factor / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D007202:Indicators and Reagents; D016898:Interferon-alpha; D050828:Protein Inhibitors of Activated STAT; D034741:RNA, Small Interfering; D011965:Receptors, Glucocorticoid; D050799:STAT5 Transcription Factor; D005576:Colforsin; D003907:Dexamethasone; D008156:Luciferases; D017868:Cyclic AMP-Dependent Protein Kinases