The p38 Mitogen-Activated Protein Kinase Regulates 11β-Hydroxysteroid Dehydrogenase Type 2 (11β-HSD2) Expression in Human Trophoblast Cells through Modulation of 11β-HSD2 Messenger Ribonucleic Acid Stability

Abstract

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.