106. IL-6 INCREASES THE SHEDDING OF NECROTIC TROPHOBLASTS FROM PLACENTAL EXPLANTS

Abstract

Preeclampsia (PE) is characterised by elevated maternal blood pressure, preceded by endothelial cell dysfunction. Dead trophoblasts, shed from the placenta may be one of the factors that trigger PE. Women with PE frequently have elevated serum levels of inflammatory markers such as, IL-6 and TNF a but their functional significance is unclear. In this study we investigated whether these or other cytokines can alter trophoblast shedding from placental explants. Placental explants were treated with 9 different cytokines for 72 hours. Shed trophoblasts then were harvested using our published method1. The numbers of trophoblasts shed were quantified by automated cell counter. Expression of active of caspases 3&7 by the shed trophoblasts was determined using a FLICA kit. The trophoblasts shed from cytokine-treated or control explants were exposed to endothelial cell monolayers and endothelial activation determined by ELISA for cell surface ICAM-1. Treatment of explants with IL-6 caused a 50% increase (p=0.001), while TNF a and TGF b 1, caused smaller significant increases in the numbers of trophoblasts shed. Trophoblasts shed from explants treated with IL-6, TGF b 1, or TGF b 3 expressed significantly less active caspases 3&7 than controls or trophoblasts shed from explants treated with other cytokines. Exposing trophoblasts shed from IL-6- or TGF b 1-treated explants to endothelial cells caused a significant (P<0.001) increase in endothelial activation. Normally trophoblasts shed from the placenta die by an apoptosis-like process and their phagocytosis by endothelial cells is silent but a shift to shedding of necrotic trophoblasts can lead to endothelial cell activation 2. However, it remains unclear what might trigger a shift from apoptotic to necrotic trophoblast death. This study suggests that IL-6 and possibly other cytokines can alter both the number and the nature of shed trophoblasts such that the trophoblast are more necrotic and their phagocytosis by maternal endothelial cells could contribute to the pathogenesis of preeclampsia.