Phosphorylation of STAT3 mediates the induction of cyclooxygenase-2 by cortisol in the human amnion at parturition
Phosphorylation of STAT3 mediates the induction of cyclooxygenase-2 by cortisol in the human amnion at parturition
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STAT3 的磷酸化介导分娩时人羊膜中皮质醇对环氧合酶 2 的诱导
DOI：
10.1126/scisignal.aac6151
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发表时间：
2015-10-27
影响因子：
7.3
通讯作者：
Sun, Kang
中科院分区：
文献类型：
--
作者：
Wang, Wangsheng;Guo, Chunming;Sun, Kang
转录因子STAT 3的激活促进了分娩过程中响应皮质醇而前馈产生的甘草素。分娩，紧急！糖皮质激素皮质醇在身体的许多组织中具有抗炎作用。然而，在分娩过程中的胎膜中，皮质醇与炎症酶考克斯-2的活性增加有关，该酶产生能促进母亲生殖平滑肌变化的肾上腺素，从而使分娩成为可能。Wang等人使用来自活跃分娩后或通过非分娩剖宫产分娩的患者的足月分娩的原代人羊膜成纤维细胞，发现糖皮质激素受体和转录因子STAT 3在编码考克斯-2的基因处的相互作用介导了一个自分泌前馈回路，该回路放大了皮质醇触发的前列腺素产生。这些发现确定了皮质醇与羊膜中炎症性前列腺素产生之间的联系机制。皮质醇在羊膜中诱导环氧合酶-2（考克斯-2）和随后产生前列腺素E2（PGE 2），这与皮质醇对大多数其他组织的作用形成对比，但皮质醇的这种促炎作用可能是人类分娩（分娩）中的关键事件。我们评估了皮质醇在原代人羊膜成纤维细胞中激活的潜在机制。羊膜成纤维细胞暴露于皮质醇导致环磷酸腺苷（cAMP）-蛋白激酶A（PKA）通路的激活，其诱导激酶SRC和STAT 3（信号转导和转录激活因子3）的磷酸化。STAT 3与糖皮质激素受体（GR）和转录因子CREB-1（cAMP反应元件结合蛋白1）在编码考克斯-2的基因的启动子处相互作用，从而促进分泌的前列腺素PGE 2的产生。PGE 2激活前列腺素受体EP 2和EP 4，其刺激cAMP-PKA信号传导。因此，皮质醇通过SRC-STAT 3-考克斯-2-PGE 2介导的反馈回路加强cAMP-PKA信号的激活。抑制STAT 3、SRC或cAMP-PKA通路减弱皮质醇刺激的羊膜成纤维细胞中考克斯-2和PGE 2产生的诱导。在人羊膜组织中，磷酸化STAT 3的量与皮质醇、考克斯-2和PGE 2的量呈正相关，并且在活跃分娩后获得的组织中比在没有分娩的情况下从剖宫产手术获得的组织中更丰富。这些结果表明，STAT 3，CREB-1，和GR的协调募集到考克斯-2的基因编码的启动子有助于前馈诱导考克斯-2的活性和前列腺素合成在羊膜分娩期间。
Activation of the transcription factor STAT3 promotes the feed-forward production of prostaglandins in response to cortisol during labor. Labor, STAT! The glucocorticoid cortisol has anti-inflammatory effects in many tissues of the body. However, in fetal membranes during labor, cortisol is associated with increased activity of the inflammatory enzyme COX-2, which produces prostaglandins that promote reproductive smooth muscle changes in the mother that enable delivery. Using primary human amnion fibroblasts from full-term births from patients who delivered after active labor or through nonlabor cesarean sections, Wang et al. found that the interaction of the glucocorticoid receptor and the transcription factor STAT3 at the gene encoding COX-2 mediates an autocrine feed-forward loop that amplifies cortisol-triggered prostaglandin production. The findings identify a mechanism linking cortisol to inflammatory prostaglandin production in the amnion. The induction of cyclooxygenase-2 (COX-2) and subsequent production of prostaglandin E2 (PGE2) by cortisol in the amnion contrast with the effect of cortisol on most other tissues, but this proinflammatory effect of cortisol may be a key event in human parturition (labor). We evaluated the underlying mechanism activated by cortisol in primary human amnion fibroblasts. Exposure of the amnion fibroblasts to cortisol led to the activation of the cyclic adenosine monophosphate (cAMP)–protein kinase A (PKA) pathway, which induced the phosphorylation of the kinase SRC and STAT3 (signal transducer and activator of transcription 3). STAT3 interacted with the glucocorticoid receptor (GR) and the transcription factor CREB-1 (cAMP response element–binding protein 1) at the promoter of the gene encoding COX-2, which promoted the production of the secreted prostaglandin PGE2. PGE2 activates the prostaglandin receptors EP2 and EP4, which stimulate cAMP-PKA signaling. Thus, cortisol reinforced the activation of cAMP-PKA signaling through an SRC–STAT3–COX-2–PGE2–mediated feedback loop. Inhibiting STAT3, SRC, or the cAMP-PKA pathway attenuated the cortisol-stimulated induction of COX-2 and PGE2 production in amnion fibroblasts. In human amnion tissue, the amount of phosphorylated STAT3 correlated positively with that of cortisol, COX-2, and PGE2, and all were more abundant in tissue obtained after active labor than in tissue obtained from cesarean surgeries in the absence of labor. These results indicated that the coordinated recruitment of STAT3, CREB-1, and GR to the promoter of the gene encoding COX-2 contributes to the feed-forward induction of COX-2 activity and prostaglandin synthesis in the amnion during parturition.