EXPRESSION OF THE HUMAN P55 AND P75 TUMOR-NECROSIS-FACTOR RECEPTORS IN PRIMARY VILLOUS TROPHOBLASTS AND THEIR ROLE IN CYTOTOXIC SIGNAL-TRANSDUCTION

Tumor necrosis factor alpha (TNF alpha) induces the apoptotic death of primary villous cytotrophoblasts in culture (Yui et al., Placenta 199 4; 15:819). Since both p55 and p75 TNF receptors (TNFRs) localize to t he villous trophoblast, we examined their roles in mediating trophobla st apoptosis. Comparison of I-125-TNF alpha binding competition by rec eptor-specific antibodies revealed 2.7-fold more TNFRp75 than TNFRp55. Immunohistochemical analysis of receptor distribution showed TNFRp75 to be expressed strongly in < 20% of cells and TNFRp55 moderately in a pproximately 50%. Culture with TNF alpha increased the percentage of c ells expressing TNFRp75 to > 40% but had little effect on TNFRp55 expr ession. Agonistic anti-TNFRp55 antibody and TNFRp55-specific TNF mutan t protein stimulated both apoptosis and loss of trophoblast viability. In contrast, TNFRp75-specific mutant TNF alpha protein failed to indu ce either of these responses. Furthermore, neither cell death nor apop tosis stimulated by wild-type TNF alpha was inhibited by an antagonist ic anti-TNFRp75 antibody. Thus, the apoptotic death of primary cytotro phoblasts is mediated almost entirely by TNFRp55, and the p75 receptor appears to have little effect on the process.