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Regulation of FasL/Fas in Human Trophoblasts: Possible Implications for Chorioamnionitis¹

Department of Pediatrics,³ Division of Neonatology and Developmental Biology, University of Pittsburgh, Magee Womens Research Institute, Pittsburgh, Pennsylvania 15213 Department of Pathology,⁴ Magee Womens Hospital, Pittsburgh, Pennsylvania 15213 Department of Pediatrics,⁵ Division of Immunogenetics (MT), University of Pittsburgh, Pittsburgh, Pennsylvania 15213

Chorioamnionitis is a common cause of premature birth and is associated with significant morbidity and mortality in the mother and infant. Preterm birth shares similarities with rejection of the fetal allograft, which is characterized by increased apoptosis of placental trophoblasts. We hypothesized that there is increased trophoblast apoptosis in chorioamnionitis and that this increased apoptosis is mediated by the Fas ligand (FasL)/Fas pathway. To test our hypothesis, we examined placental villous tissues from patients with chorioamnionitis and used the TUNEL assay to demonstrate enhanced trophoblast apoptosis in patients with chorioamnionitis. When the same samples were stained for Fas, there was increased trophoblast Fas expression in patients with chorioamnionitis. To define the mechanisms responsible for this increase in trophoblast apoptosis, we cultured villous explants from uncomplicated term placentas with proinflammatory cytokines and demonstrated a marked increase in trophoblast apoptosis. By blocking FasL, we reduced tumor necrosis factor -induced and interferon -induced apoptosis. These data suggest that chorioamnionitis is associated with increased trophoblast apoptosis and enhanced trophoblast Fas expression. As a complement to our in vivo study, we demonstrated that cytokine-induced trophoblast apoptosis is mediated in part by the FasL/Fas pathway, suggesting that cytokines promote sensitivity to Fas-mediated apoptosis. These mechanisms may be important in perpetuating inflammation in the placental microenvironment and may contribute to the pathogenesis of chorioamnionitis.

¹ Supported by grants from the Magee Womens Health Foundation, the Mario-Lemieux Centers for Patient Care and Research, and the 25 Club of Magee Womens Hospital.

² Correspondence: Dhruv Balkundi, Department of Pediatrics, Magee Womens Hospital, 300 Halket St., Pittsburgh, PA 15213. FAX: 412 641 5313; dbalkundi{at}mail.magee.edu

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