Cytokines and the regulation of apoptosis in reproductive tissues: A review

PROBLEM: To determine the role of apoptosis-regulating genes bax and bcl-2 in reproduction. METHOD OF STUDY: Review of literature and current data. RESULTS: The bcl-2 family of apoptotic regulatory gene products interact an d form dimers of anti- and pro-apoptotic proteins (e.g., bcl-2 and bar resp ectively), the ratio of which determines cell death or survival. Menses is associated with increased apoptosis in the glands, a change in bcl-2:bax ra tio and increased levels of the pro-apoptotic cytokine TNF alpha. Apoptosis occurs in all placental cell types and increases from first to third trime ster. Placental apoptosis is induced by TNF alpha in vitro and increased le vels in utero characterize most failing pregnancies, intra-uterine growth r estriction (IUGR) and labour. An increased bcl-2:bax ratio and apoptosis in the syncytiotrophoblast characterizes failing first trimester pregnancies. Apoptosis in the syncytiotrophoblast is also associated with IUCR. In a ra t model, maternal vitamin A deficiency perturbs fetal development. This is associated with aplacental infiltrate of TNF alpha positive neutrophils (da y 20) and increased placental apoptosis in areas of infiltration. A similar infiltrate occurs in a mouse model of early pregnancy loss. In the fetal m embranes, clusters of bcl-2 negative chorion trophoblast cells undergo apop tosis. This may allow passage of myometrial stimulatory factors that induce labour. CONCLUSION:The ratio of bcl-2:bax is crucial in the regulation of apoptosis , particularly in the human placenta. Changes in trophoblast apoptosis char acterize tl) early pregnancy failure, (?) IUGR and (3) pre-term and term la bour. Regardless of gestational age, TNF alpha plays a major role in the in duction of placental apoptosis.