Decidual prolactin silences the expression of genes detrimental to pregnancy
Decidual prolactin silences the expression of genes detrimental to pregnancy
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DOI：
10.1210/en.2006-1643
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发表时间：
2007-05-01
期刊：
影响因子：
4.8
通讯作者：
Gibori, Geula
中科院分区：
文献类型：
--
作者：
Bao, Lei;Tessier, Christian;Gibori, Geula
虽然催乳素（PRL）在妊娠啮齿类动物中的主要作用是维持黄体产生孕酮，但PRL或PRL受体（PRL-R）缺失小鼠的孕酮治疗无法预防胎儿丢失。我们以前已经表明，大鼠蜕膜是一个网站的催乳素的生产和行动。在这份报告中，我们研究的假设，使用PRL无效小鼠和大鼠蜕膜细胞培养，这种激素的情况下，导致在蜕膜中的基因表达对怀孕有害。结果表明，蜕膜生长是正常的PRL裸小鼠用PRL，孕酮，或其组合。然而，用孕酮处理的小鼠的蜕膜开始表达IL-6和20 α-羟基类固醇脱氢酶（20 α-HSD），这两种蛋白质在野生型小鼠的蜕膜中不存在，并且分别参与炎症和孕酮激动。IL-6和20 alpha-HSD的表达均被PRL处理阻止。我们的研究结果进一步表明，PRL抑制20 α-HSD的表达是在转录水平和蜕膜PRL（dPRL）抑制20 α-HSD启动子活性。Janus激酶2（Jak 2）的抑制剂而不是其他激酶的抑制剂可阻止20 α-HSD启动子的dPRL下调。此外，20 α-HSD启动子与组成型活性PRL-R、Jak 2或信号转导子和转录激活子5 b（Stat 5 b）的表达载体的共转染导致启动子活性的实质性抑制。两者合计，我们的调查提供了一个解释，孕酮不能维持怀孕的PRL裸小鼠，并表明，dPRL通过抑制IL-6和20 α-HSD在蜕膜中的表达在妊娠中起着重要的作用。该研究还表明，PRL信号通过Jak 2/Stat 5途径下调蜕膜中的20 α-HSD表达。
Although the main role of prolactin (PRL) in pregnant rodents is to sustain progesterone production by the corpus luteum, progesterone treatment of PRL or PRL receptor (PRL-R) null mice is unable to prevent fetal loss. We have previously shown that the rat decidua is a site of PRL production and action. In this report, we examined the hypothesis, using PRL null mice and rat decidual cell culture, that the absence of this hormone leads to the expression in the decidua of genes detrimental to pregnancy. The results show that decidual growth is normal in PRL null mice treated with PRL, progesterone, or their combination. However, the decidua of mice treated with progesterone starts expressing IL-6 and 20 alpha-hydroxysteroid dehydrogenase (20 alpha-HSD), two proteins absent from the decidua of wild-type mice and involved, respectively, in inflammation and progesterone catabolism. The expression of both IL-6 and 20 alpha-HSD is prevented by PRL treatment. Our results further suggest that PRL inhibition of 20 alpha-HSD expression is at the level of transcription and that decidual PRL (dPRL) inhibits 20 alpha-HSD promoter activity. Inhibitors of Janus kinase 2 (Jak2) but not other kinases prevent dPRL down-regulation of the 20 alpha-HSD promoter. Furthermore, cotransfection of the 20 alpha-HSD promoter with expression vectors of constitutively active PRL-R, Jak2, or signal transducer and activator of transcription 5b (Stat5b) leads to substantial inhibition of promoter activity. Taken together, our investigation provides an explanation for the inability of progesterone to sustain pregnancy in PRL null mice and suggests that dPRL plays an important role in pregnancy by repressing the expression of IL-6 and 20 alpha-HSD in the decidua. The study also demonstrates that PRL signals through the Jak2/Stat5 pathway to downregulate 20 alpha-HSD expression in the decidua.