Children's Health Research Institute & Lawson Health Research Institute, Departments of Obstetrics & Gynaecology and Physiology & Pharmacology, The University of Western Ontario, London, Ontario, Canada.
Biol Reprod. 2013 Oct 17;89(4):92. doi: 10.1095/biolreprod.113.110924. Print 2013 Oct.
The placental 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2; encoded by the HSD11B2 gene) plays a key role in fetal development, but its regulation is incompletely understood. We previously demonstrated that p38 MAPK was a positive regulator of placental 11beta-HSD2. However, it remains unknown if the other two MAPKs, ERK1/2 and JNK, were also involved. In the present study, we identified ERK1/2 as an important regulator of placental 11beta-HSD2. We showed that inhibition of ERK1/2 with the pharmacological inhibitor U0126 led to a 3-fold increase in 11beta-HSD2 activity, protein, and mRNA in primary human placental trophoblast cells. In contrast, the JNK inhibitor SP600125 had no effect. Furthermore, U0126 increased the HSD11B2 promoter activity by 300%, indicating that ERK1/2 regulates placental 11beta-HSD2 expression through a transcriptional mechanism. Importantly, siRNA-mediated knockdown of ERK1/2 caused a similar increase in 11beta-HSD2 protein. In addition, given that we previously showed that cadmium reduced placental 11beta-HSD2 expression via a transcriptional mechanism, but the signal transduction pathways involved remain unclear, we also addressed this question and found that treatment of trophoblast cells with cadmium led to rapid activation of ERK1/2. Importantly, U0126 completely abrogated the inhibitory effects of cadmium on placental 11beta-HSD2. Taken together, the present study not only identifies the ERK1/2 signaling pathway as a potent negative regulator of placental 11beta-HSD2 but also demonstrates that this pathway mediates cadmium repression of placental 11beta-HSD2. Thus, our present study reveals 11beta-HSD2 as an important target through which ERK1/2 may regulate human placental function and consequently fetal development.
胎盘 11β-羟类固醇脱氢酶 2（11β-HSD2；由 HSD11B2 基因编码）在胎儿发育中起着关键作用，但它的调节机制尚不完全清楚。我们之前的研究表明，p38 MAPK 是胎盘 11β-HSD2 的正向调节因子。然而，其他两种 MAPK，ERK1/2 和 JNK 是否也参与其中尚不清楚。在本研究中，我们确定 ERK1/2 是胎盘 11β-HSD2 的重要调节因子。我们发现，用药理学抑制剂 U0126 抑制 ERK1/2，可使原代人胎盘滋养层细胞中 11β-HSD2 的活性、蛋白和 mRNA 增加 3 倍。相比之下，JNK 抑制剂 SP600125 则没有效果。此外，U0126 使 HSD11B2 启动子活性增加了 300%，表明 ERK1/2 通过转录机制调节胎盘 11β-HSD2 的表达。重要的是，siRNA 介导的 ERK1/2 敲低也导致 11β-HSD2 蛋白的类似增加。此外，鉴于我们之前的研究表明，镉通过转录机制降低胎盘 11β-HSD2 的表达，但涉及的信号转导途径尚不清楚，我们也解决了这个问题，发现镉处理滋养层细胞可迅速激活 ERK1/2。重要的是，U0126 完全阻断了镉对胎盘 11β-HSD2 的抑制作用。综上所述，本研究不仅确定了 ERK1/2 信号通路是胎盘 11β-HSD2 的一个强有力的负调节因子，还表明该通路介导了镉对胎盘 11β-HSD2 的抑制作用。因此，本研究揭示了 11β-HSD2 是 ERK1/2 可能调节人胎盘功能并进而调节胎儿发育的重要靶标。
