SHEDDING OF TUMOR-NECROSIS-FACTOR RECEPTORS FROM PURIFIED VILLOUS TERM TROPHOBLASTS AND CYTOTROPHOBLASTIC BEWO CELLS

Within the placenta tumour necrosis factor-alpha (TNF-alpha) and its s urface receptors TNF-RI and -RII have been detected on villous cyto- a nd syncytiotrophoblast and a role in trophoblast function/differentiat ion and turnover has been suggested. Here, we show for the first time that purified villous trophoblasts and cytotrophoblastic BeWo cells ex tensively shed TNF receptors, suggesting that release of these soluble proteins is an inherent property of trophoblasts. In supernatants of purified villous trophoblasts, TNF-RI and -RII increased from undetect able levels to 307 pg/ml and 484 pg/ml, respectively, within 12 h of c ultivation. In BeWo cells, 26 pg/10(5) cells and 54 pg/10(5) cells of soluble TNF-RI and -RII, respectively, accumulated within 24 h of cult uring. While forskolin did not alter TNF-RI expression, TNF-RII mRNA, protein and secretion were selectively up-regulated in these choriocar cinoma cells suggesting that elevation of cAMP levels could modulate c ellular events by TNF-RII-mediated signal transduction, Interleukin-1, which greatly enhances TNF-alpha release from trophoblast cells, did not alter shedding of both receptors from villous trophoblasts or BeWo cells. Secretion of TNF receptors from the trophoblast may explain th e high levels of soluble TNF-binding proteins in urine of pregnant wom en and could play a role in regulating TNF-alpha activity in the place ntal villus or protection against the cytotoxic effects of the cytokin e.