Cortisol stimulates local progesterone withdrawal through induction of AKR1C1 in human amnion fibroblasts at parturition.
Cortisol stimulates local progesterone withdrawal through induction of AKR1C1 in human amnion fibroblasts at parturition.
复制标题
分娩时皮质醇通过诱导人羊膜成纤维细胞中的 AKR1C1 刺激局部黄体酮撤退。
DOI：
10.1210/endocr/bqac148
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发表时间：
2022
期刊：
影响因子：
4.8
通讯作者：
K. Sun
中科院分区：
文献类型：
--
作者：
Jiangwen Lu;Wen;Li;Luyao Wang;Yiming Lin;Fan Zhang;M. Li;Fan Pan;Wangsheng Wang;K. Sun
胎膜激活被认为是人类分娩的关键触发因素之一。前列腺素E2 （PGE2）的产生增加，是几乎所有物种分娩的共同介质，被认为是膜激活的里程碑事件之一。11β-羟基类固醇脱氢酶1 （11β-HSD1）在胎膜上也具有高的皮质醇再生能力，再生的皮质醇能诱导PGE2合成，而这一作用通常在妊娠期被黄体酮抑制。在人类分娩过程中，黄体酮的合成没有急剧下降。有趣的是，这种抑制是如何在分娩时被解除的。本研究利用人羊膜组织和胎膜中合成PGE2最多的原代羊膜成纤维细胞来研究这一问题。结果表明，11β-HSD1和羟酮还原酶家族1成员C1 （AKR1C1）的表达随着胎龄的增加而平行增加，而AKR1C1是孕酮灭活酶。皮质醇通过转录因子CCAAT增强子结合蛋白δ (C/EBPδ)诱导羊膜成纤维细胞中AKR1C1的表达。AKR1C1的抑制不仅阻断了皮质醇诱导的孕酮分解代谢，还增强了孕酮对羊膜成纤维细胞中皮质醇诱导的环氧化酶-2 （COX-2）表达的抑制作用。综上所述，我们的研究结果表明，胎膜中再生的皮质醇通过增强akr1c1介导的羊膜成纤维细胞中黄体酮的分解代谢，从而触发局部黄体酮的戒断，从而解除黄体酮对皮质醇诱导COX-2表达和PGE2合成的抑制作用，促进分娩。
Fetal membrane activation is seen as being one of the crucial triggering components of human parturition. Increased prostaglandin E2 (PGE2) production, a common mediator of labor onset in virtually all species, is recognized as one of the landmark events of membrane activation. Fetal membranes are also equipped with high capacity of cortisol regeneration by 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1), and cortisol regenerated potently induces PGE2 synthesis, an effect normally suppressed by progesterone during gestation. There is no precipitous decline of progesterone synthesis in human parturition. It is intriguing how this suppression is lifted in parturition. Here, we investigated this issue by using human amnion tissue and primary amnion fibroblasts which synthesize the most PGE2 in the fetal membranes. Results showed that the expression of 11β-HSD1 and aldo-keto reductase family 1 member C1 (AKR1C1), a progesterone inactivating enzyme, increased in parallel in human amnion tissue with gestational age toward the end of gestation and at parturition. Cortisol induced AKR1C1 expression via the transcription factor CCAAT enhancer binding protein δ (C/EBPδ) in amnion fibroblasts. Inhibition of AKR1C1 not only blocked progesterone catabolism induced by cortisol, but also enhanced the suppression of cortisol-induced cyclooxygenase-2 (COX-2) expression by progesterone in amnion fibroblasts. In conclusion, our results indicate that cortisol regenerated in the fetal membranes triggers local progesterone withdrawal through enhancement of AKR1C1-mediated progesterone catabolism in amnion fibroblasts, so that the suppression of progesterone on the induction of COX-2 expression and PGE2 synthesis by cortisol can be lifted for parturition.