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Sci Signal:上海交通大学医学院孙刚课题组发表分娩启动机制研究文章

摘要 : 2015年10月27日,Science子刊《Science Signaling》以封面论文形式发表了上海交通大学医学院附属仁济医院生殖医学中心孙刚教授实验室团队的最新研究工作。

 2015年10月27日,Science子刊《Science Signaling》以封面论文形式发表了上海交通大学医学院附属仁济医院生殖医学中心孙刚教授实验室团队的最新研究工作,研究题为“Phosphorylation of STAT3 mediates the induction of cycloxygense-2 by cortisol in the human amnion”,汪旺生博士为论文第一作者,孙刚教授为论文通讯作者。

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论文第一作者汪旺生博士介绍,人类分娩启动机制至今尚未完全解析,导致目前发生率约20%的早产和过期妊娠尚缺乏有效的防治手段,从而严重威胁新生儿的健康。分娩是一个生理应激过程,应激激素糖皮质激素在多种动物种属分娩启动中起着关键的作用,但在人类中的作用尚不明了。该团队在国家自然科学基金重点项目的资助下,发现应激激素皮质醇通过转录因子STAT3正反馈促进羊膜与分娩启动密切相关的激素前列腺素E2(PGE2)的合成。该团队发现人羊膜存在局部再生糖皮质激素皮质醇的分子机制,所产生的皮质醇与糖皮质激素受体GR结合,然后与转录因子STAT3和CREB形成复合物并结合于前列腺素合成的关键酶环氧合酶-2(COX-2)基因的启动子上促进其表达,由此产生的前列腺素PGE2通过自分泌机制磷酸化STAT3和CREB,进一步加强了皮质醇的上述作用,从而形成了羊膜PGE2产生的正反馈机制,所产生的PGE2可以扩散到子宫促进子宫平滑肌的收缩和宫颈的成熟,最终引起分娩的启动。

Science杂志社同时发表了述评"Glucocorticoid signaling drives epigenetic and transcription factors to induce key regulators of human parturition",德国马普研究所的Zannas博士和希腊雅典大学的Chrousos博士在评述中指出,这些发现使我们认识了糖皮质激素如何启动人类分娩,将来可以针对糖皮质激素信号转导的特异通路开发具有靶向性的药物,从而防治早产和过期妊娠,改善妊娠结局和新生儿健康。

原文链接:

Phosphorylation of STAT3 mediates the induction of cycloxygense-2 by cortisol in the human amnion

原文摘要:

 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.

来源: Science Signaling 浏览次数:0

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