Endogenous tumor necrosis factor alpha mediates enhanced apoptosis of cultured villous trophoblasts from intrauterine growth-restricted placentae.

Tumor necrosis factor alpha (TNFalpha) has been implicated in the abnormally high levels of trophoblast apoptosis seen in placentae from pregnancies complicated by small births. We examined the hypothesis that at physiological (35-50 mmHg) oxygen tensions, the production of TNFalpha stimulates the apoptosis of placental trophoblasts associated with infants that are intrauterine growth-restricted (IUGR). Highly purified cytotrophoblasts (CT) from IUGR-complicated pregnancies spontaneously underwent a higher rate of apoptosis after 24 h of culture at a normoxic (for villous CT) tension of 38 mmHg than did CT from normal placentae. Real-time PCR analysis of TNFalpha mRNA revealed approximately threefold higher levels in IUGR trophoblasts after culturing at a pO2 of 38 mmHg. A higher level of TNFalpha receptor p55 (which mediates apoptosis) was found in IUGR CT by western blot analysis at pO2 of <10, 38, and 140 mmHg. Neutralizing antibody to TNFalpha significantly inhibited the apoptosis of IUGR trophoblasts cultured at 38 mmHg and addition of TNFalpha significantly elevated apoptosis of normal and IUGR trophoblasts but less in IUGR cells cultured at <10 mmHg. We conclude that at physiological oxygen tensions (38 mmHg), villous CT from IUGR pregnancies, when compared with uncomplicated pregnancies, undergo more TNFalpha-induced apoptosis both because of elevated expression of TNFalpha and TNF receptor p55.