Progesterone and the Repression of Myometrial Inflammation: The Roles of MKP-1 and the AP-1 System
Progesterone and the Repression of Myometrial Inflammation: The Roles of MKP-1 and the AP-1 System
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DOI：
10.1210/me.2015-1122
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发表时间：
2015-10-01
影响因子：
--
通讯作者：
Johnson, M. R.
中科院分区：
文献类型：
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作者：
Lei, K.;Georgiou, E. X.;Johnson, M. R.
孕激素（P4）在妊娠期间维持子宫静止，其功能性退出与前列腺素合成增加和分娩开始有关。在原代人子宫肌层细胞中，糖皮质激素受体（GR）而不是P4受体介导P4对IL-1 β诱导的环氧化酶-2（考克斯-2）表达的拮抗作用，COX-2是前列腺素合成中的限速酶。我们现在报道，P4也通过GR诱导MAPK磷酸酶（MKP）-1，并且MKP-1的敲低损害P4抑制IL-1 β依赖性考克斯-2诱导的能力。微阵列分析显示，P4优先抑制激活蛋白-1-应答基因对IL-1 β的应答。与这些观察结果一致，我们发现P4降低c-Jun活化的能力在GR以及MKP-1敲低后丧失。有趣的是，人子宫肌层细胞中的c-Jun水平在GR和MKP-1敲低后下降，这表明存在激活蛋白-1反馈环。这得到了我们的观察结果的支持，即c-Jun水平在用佛波醇12-肉豆蔻酸酯13-乙酸酯（c-Jun N-末端激酶的有效激活剂）处理的原代子宫肌层细胞中最初上升后下降。最后，我们表明，MKP-1是一个中间P4介导的抑制一些，但不是所有的IL-1 β反应基因。例如，IL 11和IRAK 3的P4抑制在MKP-1敲低后得以维持。总之，数据显示P4通过GR驱动MKP-1表达，MKP-1反过来抑制IL-1 β依赖性c-Jun活化和考克斯-2表达。
Progesterone (P4) maintains uterine quiescence during pregnancy and its functional withdrawal is associated with increased prostaglandin synthesis and the onset of labor. In primary human myometrial cells, the glucocorticoid receptor (GR) rather than the P4 receptor mediates P4 antagonism of IL-1 beta-induced cyclooxygenase-2 (COX-2) expression, the rate-limiting enzyme in prostaglandin synthesis. We now report that P4 also acts via GR to induce MAPK phosphatase (MKP)-1 and knockdown of MKP-1 impairs the ability of P4 to repress IL-1 beta-dependent COX-2 induction. Microarray analysis revealed that P4 repressed preferentially activator protein-1-responsive genes in response to IL-1 beta. Consistent with these observations, we found that the ability of P4 to reduce c-Jun activation was lost upon GR as well as MKP-1 knockdown. Interestingly, c-Jun levels in human myometrial cells declined upon GR and MKP-1 knockdown, which suggests the presence of an activator protein-1 feedback loop. This is supported by our observation that c-Jun levels declined after an initial rise in primary myometrial cells treated with phorbol 12-myrisatate 13-acetate, a potent activator of c-Jun N-terminal kinase. Finally, we show that MKP-1 is an intermediate in P4-mediated repression of some but not all IL-1 beta-responsive genes. For example, P4 repression of IL11 and IRAK3 was maintained upon MKP-1 knockdown. Taken together, the data show that P4 acts via GR to drive MKP-1 expression, which in turn inhibits IL-1 beta-dependent c-Jun activation and COX-2 expression.