Cross-Talk between cAMP and MAPK Pathways in HSD11B2 Induction by hCG in Placental Trophoblasts

Qun Shu,Kang Sun,Jianneng Li,Chao Liu,Wangsheng Wang,Wenjiao Li,Kang Sun

doi:10.1371/journal.pone.0107938

Abstract

Overexposure of the fetus to glucocorticoids in gestation is detrimental to fetal development. The passage of maternal glucocorticoids into the fetal circulation is governed by 11beta-Hydroxysteroid Dehydrogenase Type 2 (HSD11B2) in the placental syncytiotrophoblasts. Human chorionic gonadotropin (hCG) plays an important role in maintaining placental HSD11B2 expression via activation of the cAMP pathway. In this study, we investigated the relationship between the activation of the cAMP pathway by hCG and subsequent phosphorylation of extracellular signal-regulated kinase1/2 (ERK1/2) or p38 mitogen-activated protein kinase (MAPK) pathways in the regulation of placental HSD11B2 expression in human placental syncytiotrophoblasts. We found that treatment of the placental syncytiotrophoblasts with either hCG or dibutyl cAMP (dbcAMP) could promote the phosphorylation of p38 and ERK1/2. Inhibition of p38 MAPK with SB203580 not only reduced the basal HSD11B2 mRNA and protein levels but also attenuated HSD11B2 levels induced by either hCG or dbcAMP. By contrast, inhibition of ERK1/2 with PD98059 increased the basal mRNA and protein levels of HSD11B2 and had no effect on HSD11B2 mRNA and protein levels induced by either hCG or dbcAMP. These data suggest that p38 MAPK is involved in both basal and hCG/cAMP-induced expression of HSD11B2, and ERK1/2 may play a role opposite to p38 MAPK at least in the basal expression of HSD11B2 in human placental syncytiotrophoblasts and that there is complicated cross-talk between hCG/cAMP and MAPK cascades in the regulation of placental HSD11B2 expression.

Highlights

Appropriate amounts of glucocorticoids are crucial for the normal development and maturation of the fetus [1]
Treatment of the syncytiotrophoblasts with dibutyl cyclic AMP significantly increased the phosphorylation of p38 and Extracellular signal-regulated kinase1/2 (ERK1/2) mitogen-activated protein kinase (MAPK) in a timedependant manner with the maximal effect observed at 30 min (Fig. 1A and Fig. 1B)
Role of p38 MAPK in the induction of HSD11B2 and SP1 by Human chorionic gonadotropin (hCG)/dibutyl cAMP (dbcAMP) in human placental syncytiotrophoblasts SB203580 (10 mM), an inhibitor of p38 MAPK, decreased the basal levels of HSD11B2, SP1 mRNA (Fig. 2A and Fig. 2B) and protein (Fig. 3A and Fig. 3B), and the levels of HSD11B2, SP1 mRNA and protein induced by either hCG (10 IU/ml) or dbcAMP (100 mM) significantly (Fig. 2 and Fig. 3), suggesting that the induction of HSD11B2 and SP1 expression by hCG/cAMP is, at least in part, mediated via p38 MAPK in human placental syncytiotrophoblasts

Summary

Introduction

Appropriate amounts of glucocorticoids are crucial for the normal development and maturation of the fetus [1]. Despite the adverse effects of excessive glucocorticoids in fetal development, maternal adrenal glands undergo progressive hyperplasia and secrete increasing amounts of glucocorticoids throughout gestation [4]. The production of glucocorticoids by the fetal adrenal glands tends to increase at late gestation, the maternal plasma concentration of cortisol is 5– 10 times higher than that of the fetal plasma [6]. To finely tune the passage of maternal glucocorticoids which are highly lipidpermeable steroids, into the fetal circulation, there exists a glucocorticoid inactivating enzyme, i.e. 11beta-Hydroxysteroid Dehydrogenase Type 2 (HSD11B2) [7,8,9] which converts biologically active cortisol in maternal circulation into inactive cortisone, in the syncytial layer of the placental villi [10,11]. Understanding of the regulation of placental HSD11B2 expression may represent a key component in the overall understanding of the molecular mechanisms that govern fetal development

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Conclusion