Endocrine Abstracts

The formation of the placental syncytiotrophoblast through trophoblast differentiation is a key cellular event, essential for successful embryonic implantation, oxygen/nutrient transport and secretion of placental hormones necessary for fetal development. Trophoblast differentiation alters expression of various molecules with important roles in placental biology, including 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), the major component of the placental glucocorticoid (GC) barrier that limits exposure of the fetus and placenta to maternal GC. The endocrine effectors and molecular signaling pathways involved are not fully characterised. To investigate 11β-HSD2 regulation of expression, we employed the BeWo choriocarcinoma cell line, able to differentiate upon forskolin treatment and stimulation of district signaling cascades including the cAMP/PKA and ERK1/2 and P38 MAPKs¹. Our results showed that BeWo trophoblasts express low levels of 11β-HSD2. Protein expression was significantly enhanced when specific inhibitors were used to inhibit activity of the PI3K-Akt-eNOS pathway that involves molecules recently identified as negative regulators of forskolin-induced BeWo fusion². In contrast, inhibition of ERK1/2 and P38 MAPK attenuated 11β-HSD2 mRNA and protein expression. BeWo trophoblast 11β-HSD2 expression was also regulated by corticotrophin releasing hormone (CRH): interestingly, CRH treatment up-regulated 11β-HSD2 protein without affecting mRNA levels, raising the possibility of non-transcriptional effects of CRH targeting protein stability. Moreover, similar effects of CRH were demonstrated in experiments employing placental explants and appear to involve regulation of the ERK1/2, β38 MAPK and Akt pathways. Thus, this data identified in the BeWo trophoblasts novel signaling regulators of placental 11β-HSD2 expression and placental actions of CRH that might be important in the control of cellular sensitivity to GC with potentially important pathophysiological implications.

Delidaki et al. 2011 Mol Cell Endocrinol. 2011 332 213–20.

Vatish et al. 2012 PLOS One, in press.

Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.

Funding: This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.