Endothelial cell death induced by tumor necrosis factor-alpha is inhibited by the Bcl-2 family member, A1

Endothelial cells play a central role in the inflammatory process, Tumor necrosis factor-cy (TNF) is a multifunctional cytokine which elicits many of the inflammatory responses of endothelial cells, While TNF directly causes apoptosis of tumor cells and virally infected cells, normal cells are generally resistant. However, most resistant cells, including human endothelial cells, can be rendered susceptible to TNF by inhibiting RNA or protein synthesis. This finding suggests that TNF provides a cell survival signal in addition to a death signal. We have previously cloned a human Bcl-2 homologue, Al, and shown that it is specifically induced by proinflammatory cytokines but not by endothelial growth factors. In this study, we show that retroviral-mediated transfer of the Al cDNA to a human microvascular endothelial cell line provides protection against cell death initiated by TNF in the presence of actinomycin D. The induction of Al by TNF in this system is mediated via a protein kinase C pathway, Since TNF signaling has also been shown to proceed via ceramides, we tested whether exogenous ceramides could induce Al, Our findings indicate that ceramides do not induce Al but do up-regulate c-jun and induce endothelial death. Ceramide-activated endothelial death is also inhibited by Al, suggesting that TNF may initiate divergent survival and death pathways via separate lipid second messengers.