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

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.

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► These studies explore interactions between interferon-alpha-induced JAK–STAT signaling, glucocorticoid receptor signaling, and cAMP/protein kinase A signaling.