A role for interleukin-6 in spreading endothelial cell activation after phagocytosis of necrotic trophoblastic material: implications for the pathogenesis of pre-eclampsia

Pre-eclampsia is characterized by systemic maternal endothelial dysfunction that precedes the onset of clinical symptoms. The cause of the dysfunction is not clear but the number and the nature of trophoblasts shed from the placenta may be altered in pre-eclamptic pregnancies. These dead trophoblasts become trapped in the pulmonary capillaries and may then be phagocytosed by endothelial cells. Phagocytosis of necrotic, but not apoptotic, trophoblasts results in endothelial cell activation. We have explored the hypothesis that activation can subsequently spread to other endothelial cells via soluble factors without the need for direct contact with shed trophoblasts. Conditioned medium from endothelial cells that had phagocytosed necrotic, but not apoptotic, trophoblasts was shown to activate fresh endothelial cells due, in large part, to IL-6 secreted into the conditioned medium. The amount of IL-6 secreted in response to phagocytosis of necrotic trophoblasts was similar to the levels of IL-6 found by others in the blood of pre-eclamptic women and was substantially more than the level of IL-6 which has been reported to induce symptoms of pre-eclampsia in pregnant rats. We demonstrated that phagocytosis of both a trophoblast cell line as well as trophoblasts shed from human placentae, had this effect on two different types of endothelial cells. The role of IL-6 in endothelial cell activation was confirmed using recombinant IL-6 and neutralizing antibodies against IL-6 and the IL-6 receptor. Thus, IL-6 secreted by pulmonary endothelial cells after they have phagocytosed necrotic trophoblasts that are trapped in the pulmonary capillaries could activate endothelial cells in other remote vascular beds, contributing to the systemic activation of the endothelium that is a hallmark of pre-eclampsia. Copyright (C) 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.