Up-regulation of the progesterone receptor (PR)-C isoform in laboring myometrium by activation of nuclear Factor-κB may contribute to the onset of labor through inhibition of PR function
Up-regulation of the progesterone receptor (PR)-C isoform in laboring myometrium by activation of nuclear Factor-κB may contribute to the onset of labor through inhibition of PR function
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DOI：
10.1210/me.2005-0242
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发表时间：
2006-04-01
影响因子：
--
通讯作者：
Mendelson, CR
中科院分区：
文献类型：
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作者：
Condon, JC;Hardy, DB;Mendelson, CR
孕激素通过孕激素受体（PR）发挥作用，在维持妊娠期子宫静止中起着关键作用。在本研究中，我们测试了这一假设，即PR的反式激活能力是下调在子宫肌层在任期内的子宫PR亚型比例的变化，导致局部激活的核因子（NF）-κ B途径。在人子宫肌层细胞中过表达截短的PR-C亚型抑制PR-B反式激活。通过免疫印迹和定量PCR（Q-PCR）对分娩和未分娩孕妇的子宫底和子宫下段肌层以及妊娠晚期妊娠小鼠子宫中PR亚型PR-A、PR-B和PR-C的表达进行了表征。我们观察到PR-C和转录活性PR-B的水平显着增加，特别是在子宫底肌层的妇女在劳动。在妊娠小鼠子宫中，PR-B和PR-C的水平也在孕后15天和足月之间增加，而PR-A的表达在孕后19天显著上调。在子宫内注射表面活性蛋白A的小鼠子宫组织和培养的人子宫肌层和T47 D乳腺癌细胞的研究中，观察到PR亚型表达的上调响应于NF-κ B途径的激活。染色质免疫沉淀分析显示IL-1 β诱导NF-κ B与PR启动子结合。总的来说，这些发现表明，NF-κ B B激活的抑制性PR亚型表达的上调，在劳动的人眼底和妊娠小鼠子宫近期可能会抑制PR反式激活，从而导致子宫静止的损失和劳动的开始。
Progesterone acting via the progesterone receptor ( PR) plays a critical role in maintaining uterine quiescence during pregnancy. In the present study, we tested the hypothesis that the transactivating capability of the PR is down-regulated in the myometrium at term by a change in uterine PR isoform ratio resulting from local activation of the nuclear factor (NF)-kappa B pathway. Overexpression of the truncated PR-C isoform in human myometrial cells inhibited PR-B transactivation. Expression of PR isoforms, PR-A, PR-B, and PR-C, was characterized by immunoblotting and quantitative PCR (Q-PCR) in fundal and lower uterine segment myometrium from pregnant women in labor and not in labor and in the pregnant mouse uterus during late gestation. We observed a marked increase in levels of PR-C and transcriptionally active PR-B specifically in fundal myometrium of women in labor. In pregnant mouse uterus, levels of PR-B and PR-C also increased between 15 days post coitum and term, whereas expression of PR-A was dramatically up-regulated at 19 days post coitum. In studies of uterine tissues of mice injected intraamniotically with surfactant protein A and of human myometrial and T47D breast cancer cells in culture, up-regulation of PR isoform expression was observed in response to activation of the NF-kappa B pathway. Chromatin immunoprecipitation analysis revealed IL-1 beta induced binding of NF-kappa B to the PR promoter. Collectively, these findings suggest that up-regulation of inhibitory PR isoform expression by NF-kappa B activation in both laboring human fundus and pregnant mouse uterus near term may inhibit PR transactivation and thereby lead to a loss of uterine quiescence and the onset of labor.