Activation of cAMP-protein kinase A abrogates STAT5-mediated inhibition of glucocorticoid receptor signaling by interferon-alpha.
Activation of cAMP-protein kinase A abrogates STAT5-mediated inhibition of glucocorticoid receptor signaling by interferon-alpha.
复制标题
cAMP-蛋白激酶 A 的激活消除了 STAT5 介导的干扰素-α 对糖皮质激素受体信号传导的抑制。
DOI：
10.1016/j.bbi.2011.07.227
复制
发表时间：
2011
期刊：
影响因子：
--
通讯作者：
Miller,AndrewH
中科院分区：
文献类型：
--
作者：
Pace,ThaddeusWW;Hu,Fang;Miller,AndrewH
已发现IFN-α通过激活Janus激酶-信号转导子和转录激活子（JAK-STAT）炎症信号传导途径来抑制糖皮质激素受体（GR）功能。相反，通过刺激蛋白激酶A（PKA），cAMP已被证明可以增强GR功能，并可以抑制炎症信号。因此，我们研究了cAMP-PKA通路激活的增加是否可以逆转IFN-α诱导的GR功能抑制，以及cAMP-PKA活性的降低是否可能加剧IFN-α对GR的作用。在海马HT 22细胞中，毛喉素（10μM）激活cAMP可以逆转mIFN-α（1000 U/ml）对地塞米松（DEX）诱导的MMT-荧光素酶活性的抑制作用。Forskolin处理还阻断了IFN-α诱导的磷酸化STAT 5（pSTAT 5）的活化以及用IFN-α和DEX处理的HT 22细胞核中pSTAT 5和GR之间的抑制性蛋白质-蛋白质相互作用。毛喉素的这些作用通过PKA抑制剂H89的共同给药而逆转。相反，IFN-α与H89或针对PKA的α和β催化亚基同种型的siRNA治疗的组合导致对HT 22细胞中DEX诱导的GR活性的加性抑制作用。综上所述，这些发现表明mIFN-α和STAT 5对GR信号传导的抑制可以通过激活cAMP-PKA途径来逆转，而PKA活性降低会增加IFN-α对GR功能的抑制作用。鉴于在重度抑郁症患者中发现PKA活性降低，这些数据表明抑郁症患者可能容易受到细胞因子对GR的影响，cAMP-PKA激动剂可能有助于逆转抑郁症和炎症增加患者的糖皮质激素抵抗。
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 (10μM) 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.