TROPHOBLAST-DERIVED TRANSFORMING GROWTH FACTOR-BETA-1 SUPPRESSES CYTOKINE-INDUCED, BUT NOT GONADOTROPIN-RELEASING HORMONE-INDUCED, RELEASE OF HUMAN CHORIONIC-GONADOTROPIN BY NORMAL HUMAN TROPHOBLASTS

Using a transforming growth factor-beta (TGF-beta)-sensitive cell line, Mv1Lu (or CCL 64), we demonstrated that trophoblasts predominantly produced a latent form of TGF-beta. After converting latent TGF-beta to active TGF-beta in vitro by acid (pH 2.5), alkali (pH 10.0), or heat (90 C; 10 min) treatment, addition of rabbit anti-TGF-beta(1) antiserum resulted in the elimination of TGF-beta activity, thus suggesting that trophoblasts produced at least a certain amount of latent TGF-beta(1). To investigate the role of TGF-beta(1) in placental hormonogenesis, we first studied the effect of recombinant (r) TGF-beta(1) on the production of interleukin-6 (IL-6) and hCG by trophoblasts. rTGF-beta(1) exerted no inhibitory activity on IL-6 and hCG production. The effect of rTGF-beta(1) on cytokine-induced IL-6 and hCG release was then examined. While rTGF-beta(1) failed to inhibit basal hCG secretion, it did inhibit recombinant tumor necrosis factor-alpha (rTNF-alpha)-induced IL-6 release as well as rTNF-alpha- and rIL-6-induced hCG release in a dose-dependent manner. However, rIL-1-alpha-induced IL-6 and hCG release was remarkably sensitive to rTGF-beta(1)-mediated suppression. In contrast, GnRH-induced hCG release, the response of which is independent of the IL-6 and IL-6 receptor system in trophoblasts, was completely resistant to rTGF-beta(1). Thus, trophoblast-derived TGF-beta(1) is an important regulatory molecule of cytokine-dependent, but not cytokine-independent, hCG release, possibly by converting latent TGF-beta to active TGF-beta at the local site of trophoblasts.