Sharma Anju, Guan Haiyan, Yang Kaiping
Department of Obstetrics and Gynaecology, Children's Health Research Institute and Lawson Health Research Institute, The University of Western Ontario, London, Ontario, Canada.
Endocrinology. 2009 Sep;150(9):4278-86. doi: 10.1210/en.2009-0479. Epub 2009 Jun 4.
The placental 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2; encoded by the HSD11B2 gene) has emerged as a key player in controlling fetal development, but its regulation is incompletely understood. Here we identified p38 MAPK as an important regulator of placental 11beta-HSD2. We showed that inhibition of p38 MAPK with the pharmacological inhibitor SB202190 led to an approximately 50% reduction in 11beta-HSD2 activity, protein, and mRNA in primary human placental trophoblast cells. Furthermore, the effect of SB202190 was confirmed by the use of two additional p38 inhibitors, SB203580 and SB220025. In addition, SB202190 decreased the half-life of 11beta-HSD2 mRNA without altering the HSD11B2 promoter activity, indicating that p38 MAPK regulates placental 11beta-HSD2 expression through modulation of 11beta-HSD2 mRNA stability. Importantly, small interfering RNA-mediated knockdown of p38alpha caused a 50% reduction in 11beta-HSD2 activity, suggesting that p38alpha is the primary p38 isoform involved. Taken together, these findings suggest a novel pathway controlling placental 11beta-HSD2 expression resulting from the activation of p38 MAPK. Given that p38alpha is abundantly expressed in the human placenta in which its function is largely unknown, our present study also reveals 11beta-HSD2 as an important target through which p38alpha may regulate human placental function and consequently fetal growth and development.
胎盘2型11β-羟基类固醇脱氢酶（11β-HSD2；由HSD11B2基因编码）已成为控制胎儿发育的关键因子，但其调控机制尚未完全明确。在此，我们确定p38丝裂原活化蛋白激酶（p38 MAPK）是胎盘11β-HSD2的重要调节因子。我们发现，用药物抑制剂SB202190抑制p38 MAPK可使原代人胎盘滋养层细胞中的11β-HSD2活性、蛋白和mRNA水平降低约50%。此外，另外两种p38抑制剂SB203580和SB220025的使用证实了SB202190的作用。此外，SB202190降低了11β-HSD2 mRNA的半衰期，但未改变HSD11B2启动子活性，表明p38 MAPK通过调节11β-HSD2 mRNA稳定性来调控胎盘11β-HSD2的表达。重要的是，小干扰RNA介导的p38α敲低导致11β-HSD2活性降低50%，提示p38α是主要参与的p38亚型。综上所述，这些发现提示了一条由p38 MAPK激活所导致的控制胎盘11β-HSD2表达的新途径。鉴于p38α在人胎盘中大量表达，但其功能 largely unknown（此处原文有误，推测为“很大程度上未知”），我们目前的研究还揭示11β-HSD2是p38α可能调节人胎盘功能从而影响胎儿生长发育的一个重要靶点。
