Corticotropin-releasing factor, urocortin and endothelin-1 stimulate activin A release from cultured human placental cells

Human placenta produces activin A, a glycoprotein belonging to the transforming growth factor beta superfamily, which modulates several placental immune and endocrine functions. However, substances involved in controlling placental activin A production are not yet completely elucidated. The aim of the present study was to investigate the effects of placental products, corticotropin-releasing factor (CRF), urocortin, prostaglandin E(2) (PGE(2)) and endothelin-1 (ET-1) on activin A release from cultured human placental cells. Placental tissue was collected at term from normal pregnancies and a trophoblast-enriched cell preparation was cultured for 48 h. The test substances were applied (concentration from 10(-9)-10(-7)M) and the medium was harvested after 3 h incubation; vehicle-treated cells (controls) were present in each experiment. Activin A concentrations in culture medium were measured by using a specific two-site enzyme immunoassay. The addition of CRF resulted in a dose-related increase of activin A concentrations (P < 0.01). The stimulatory effect of CRF was significantly reversed by alpha-helical CRF(9-41), the CRF receptor antagonist. Urocortin showed a stimulating effect on activin A release from placental cells (P < 0.05) but not dose-related; the effect of urocortin was reversed by an equimolar dose of CRF antagonist, astressin. ET-1 significantly increased activin A concentrations in the culture medium only at the highest concentration, 10(-7)M (P < 0.05). No difference in activin A release was observed after incubating the cells with PGE(2). The evidence that CRF, urocortin and ET-1 stimulate activin A secretion from cultured placental cells suggests that these vasoactive factors may affect the changes of placental activin A secretion in pre-eclamptic woman.