Progesterone-induced activation of membrane-bound progesterone receptors in murine macrophage cells.
Progesterone-induced activation of membrane-bound progesterone receptors in murine macrophage cells.
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DOI：
10.1530/joe-14-0470
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发表时间：
2015-02
期刊：
影响因子：
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通讯作者：
Hirsch E
中科院分区：
文献类型：
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作者：
Lu J;Reese J;Zhou Y;Hirsch E
分娩过程在很大程度上是由巨噬细胞介导的炎症过程。孕酮在妊娠期间维持子宫静止，孕酮的功能性退出通常由核孕酮受体（nPRs）调节，导致分娩。孕酮可以影响巨噬细胞的功能，尽管在这些免疫细胞中缺乏nPRs的表达。因此，在本研究中，我们研究了推测的膜相关孕酮受体的激活对巨噬细胞（分娩的关键细胞）功能的影响，并讨论了这些发现对妊娠和分娩的意义。在小鼠巨噬细胞（RAW264.7）中，通过与BSA （P4BSA, 1.0×10−7 mol/l）结合而修饰为仅在细胞外有活性的孕酮激活mPRs，导致mRNA表达谱的促炎变化，环氧化酶2 （Ptgs2）、Il1B和Tnf的表达显著上调，膜孕酮受体α (Paqr7)和催产素受体（Oxtr）的表达下调。MEK 1/2抑制剂PD98059预处理可显著降低p4bsa诱导的Il1B、Tnf和Ptgs2 mRNA。H89抑制蛋白激酶A （PKA）可阻断p4bsa诱导的il - 1b和Tnf mRNA水平。P4BSA诱导MEK1/2和cAMP响应元件结合蛋白（CREB， PKA的下游靶点）的快速磷酸化。PD98059和H89预处理分别抑制了这种磷酸化，表明MEK1/2和PKA是参与mPR信号传导的两个成分。综上所述，这些数据表明，巨噬细胞中膜孕酮受体α表达和信号传导的变化与炎症反应有关；这些变化可能会导致与分娩相关的黄体酮的功能性戒断。
Parturition is an inflammatory process mediated to a significant extent by macrophages. Progesterone maintains uterine quiescence in pregnancy, and a proposed functional withdrawal of progesterone classically regulated by nuclear progesterone receptors (nPRs) leads to labor. Progesterone can impact the functions of macrophages despite the reported lack of expression of nPRs in these immune cells. Therefore, in this study we investigated the effects of the activation of the putative membrane-associated progesterone receptor on the function of macrophages (a key cell for parturition) and discuss the implications of these findings for pregnancy and parturition. In murine macrophage cells (RAW264.7), activation of mPRs by progesterone modified to be active only extracellularly by conjugation to BSA (P4BSA, 1.0×10−7 mol/l) caused a pro-inflammatory shift in mRNA expression profile, with significant up-regulation of the expression of cyclooxygenase 2 (Ptgs2), Il1B, and Tnf and down-regulation of membrane progesterone receptor alpha (Paqr7) and oxytocin receptor (Oxtr). Pretreatment with PD98059, a MEK 1/2 inhibitor, significantly reduced P4BSA-induced Il1B, Tnf and Ptgs2 mRNA. Inhibition of protein kinase A (PKA) by H89 blocked P4BSA-induced Il1B and Tnf mRNA levels. P4BSA induced rapid phosphorylation of MEK1/2 and cAMP responsive element binding protein (CREB, a downstream target of PKA). This phosphorylation was inhibited by pretreatment with PD98059 and H89, respectively, revealing that MEK1/2 and PKA are two of the components involved in mPR signaling. Taken together, these data demonstrate that changes in membrane progesterone receptor alpha expression and signaling in macrophages are associated with the inflammatory responses; and that these changes might contribute to the functional withdrawal of progesterone related to labor.