LIPOPOLYSACCHARIDE INDUCES THE ANTIAPOPTOTIC MOLECULES, A1 AND A20, IN MICROVASCULAR ENDOTHELIAL-CELLS

The effect of lipopolysaccharide (LPS) on endothelial cells is a key c omponent of the inflammatory response seen in Gram-negative sepsis. LP S does not cause death of cultured human endothelial cells. However, w hen the expression of new proteins is inhibited by cycloheximide, micr ovascular endothelial cells in culture undergo apoptosis. This finding suggests that LPS induces apoptotic and antiapoptotic pathways, with the antiapoptotic response being dependent on the synthesis of new pro teins. Concurrent activation of apoptotic and antiapoptotic pathways h as previously been documented for tumor necrosis factor (TNF). In the case of TNF, the antiapoptotic signal has been attributed to at least two cytoprotective proteins: the Bcl-2 homologue, Al, and the zinc-fin ger protein, A20. In this study, we demonstrate that both these molecu les are induced in microvascular endothelial cells by LPS. Enforced ov erexpression of either Al or A20 inhibits LPS and cycloheximide-initia ted apoptosis. Induction of Al and A20 does not require synthesis of i ntermediary proteins, but is dependent on the presence of soluble CD14 . In addition, we show that inhibition of signaling by the transcripti on factor, NF-kappa B, blocks accumulation of Al and A20 mRNA. Taken t ogether, our findings suggest that LPS directly induces expression of the cytoprotective proteins, Al and A20, via a CD14-dependent pathway requiring activation of NF-kappa B. (C) 1998 by The American Society o f Hematology.