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Enhanced Human Decidual Cell-Expressed FKBP51 May Promote Labor-Related Functional Progesterone Withdrawal

机译:增强的人类蜕膜细胞表达的FKBP51可能促进与劳动有关的功能性孕酮的退出

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Sustained plasma progesterone (P4) levels suggest initiation of human term Labor by functional P4 withdrawal, reflecting reduced progesterone receptor (PR) and/or glucocorticoid receptor (GR) expression or activity. The steroid-induced immunophilin cochaperone FKBP51 inhibits PR- and GR-mediated transcription, suggesting a labor-initiating role. Gestational age-matched decidual sections were immunostained for FKBP51 and decidual cell (DC) and interstitial trophoblast (IT) markers, vimentin and cytokeratin, respectively. Term DC cultures were incubated with vehicle (control), estradiol (E-2) with or without medroxyprogesterone acetate, dexamethasone (Dex), or Organon 2058. FKBP51 histologic scoring was significantly higher in DC nuclei during labor versus prelabor decidua, whereas FKBP51 immunostaining was undetected in interstitial trophoblasts (P < 0.05). In term DC cultures, E-2 + medroxyprogesterone acetate or E-2 + Dex enhanced FKBP51 expression (P < 0.01), whereas E-2 + Organon 2058 inhibited PR expression (P < 0.05), and E-2 + Dex inhibited GR expression (P < 0.05). Unlike term DCs, FKBP51 was undetected in control or Dex-treated cultured third-trimester trophoblasts. Electrophoretic mobility shift assays revealed that FKPB51 overexpression or silencing in cultured DCs altered PR-DNA binding. Increased FKBP51 levels in term DCs during labor complement our prior in situ observations of significantly lower PR in labor versus prelabor DCs. In a milieu of sustained plasma P4 levels, these reciprocal changes will amplify functional P4 withdrawal in DCs via FKBP51-mediated PR resistance coupled with declining PR levels, whereas the Lack of FKBP51 expression in interstitial trophoblasts suggests unopposed constitutive GR action.
机译:血浆血浆孕酮(P4)的持续升高表明通过功能性P4戒断可以引发人类足月分娩,这反映出孕酮受体(PR)和/或糖皮质激素受体(GR)的表达或活性降低。类固醇诱导的亲免蛋白伴侣蛋白FKBP51抑制PR和GR介导的转录,提示其起劳动作用。对胎龄匹配的蜕膜切片进行了FKBP51和蜕膜细胞(DC)和间质滋养细胞(IT)标记,波形蛋白和细胞角蛋白的免疫染色。将术语DC培养物与媒介物(对照),雌二醇(E-2),有或没有乙酸甲羟孕酮,地塞米松(Dex)或Organon 2058一起孵育。与分娩前的蜕膜相比,分娩过程中DC核的FKBP51组织学评分明显较高,而FKBP51免疫染色间质滋养细胞中未检出(P <0.05)。在长期DC培养中,E-2 +醋酸甲羟孕酮或E-2 + Dex增强FKBP51表达(P <0.01),而E-2 + Organon 2058抑制PR表达(P <0.05),而E-2 + Dex抑制GR。表达(P <0.05)。与术语DC不同,在对照或经Dex处理的培养的第三代滋养细胞中未检测到FKBP51。电泳迁移率变动分析表明,培养的DC中FKPB51的过表达或沉默改变了PR-DNA的结合。在分娩期间足月DC中FKBP51水平的增加补充了我们先前的原位观察,即与分娩前DC相比,分娩PR显着降低。在血浆P4持续水平的环境中,这些相互的变化将通过FKBP51介导的PR抗性和PR水平的下降,放大DC中功能性P4的撤出,而间质滋养细胞中FKBP51表达的缺乏则表明本构性GR的作用是相反的。

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