Effect of cytokines and growth factors on the secretion of inhibin A, activin A and follistatin by term placental villous trophoblasts in culture.

Objective: Maternal serum inhibin A and activin A are higher in pre-eclampsia than in normal pregnancy. The placenta is a source of these proteins in pregnancy. The aim of this study was to investigate the effect of growth factors and proinflammatory cytokines that are raised in pre-eclampsia on the secretion of dimeric inhibin A, activin A and follistatin by villous cytotrophoblasts in culture. Design and methods: Villous cytotrophoblasts were prepared from term placentae and cultured in serumfree media. Cells were treated with increasing concentrations of tumour necrosis factor (TNF)-a, interleukin (IL)-1b, transforming growth factor (TGF)-b1, granulocyte and monocyte colonystimulating factor (GMCSF), inhibin A, activin A and follistatin for 2 days. Culture supernatants were assayed for human chorionic gonadotrophin (hCG), inhibin A, activin A and follistatin as appropriate. Experiments were repeated at least three times with each cytokine or growth factor and the data pooled. Results: Cytotrophoblasts syncytialise and spontaneously secrete hCG, inhibin A and activin A in culture. Follistatin levels were ,20 pg/ml in most experiments. Activin A secretion was increased in culture in a dose-dependent manner by IL-1b (,150%, P , 0:05U; TNF-a (,35%, Pa 0:02U and GMCSF (,100%, P , 0:01U: hCG secretion was inhibited in a dose-dependent manner by TNF-a (50%, P , 0:05U: Inhibin A was stimulated by IL-1b (,30%, Pa 0:05U: Inhibin A, activin A, follistatin or TGF-b1 did not have a significant effect on any measured parameters. Conclusions: These data show that inflammatory cytokines increase the secretion of activin A by trophoblasts in culture. The presence of very low levels, or no follistatin (,20 pg/ml) in the culture media suggests ‘free’ activin A could have autocrine/paracrine effects on cytotrophoblasts. Inhibin A secretion was stimulated by IL-1b. However, absence of an effect by the other cytokines investigated on inhibin A in this study suggests that the mechanism(s) involved in increasing maternal circulating levels of inhibin A and activin A in pre-eclampsia are controlled differentially.