Cloning of a human Bcl-2 homologue: Inflammatory cytokines induce human A1 in cultured endothelial cells

Abstract

Bcl-2 is an intracellular membrane-associated protein that functions to block programmed cell death. Despite recurrent exposure to cellular toxins from the circulation and tissue, endothelial cells are remarkably resistant to cell death. Because Bcl-2 protein levels are low or undetectable in endothelial cells, we postulated that other members of the growing Bcl-2 family would be present in endothelial cells to provide protection against apoptosis. Degenerate primers to two conserved regions of the Bcl-2 family were used to amplify potential homologues in endothelial cells. This strategy resulted in the isolation of a human Bcl-2 homologue related to murine A1, a recently identified member of this family. We show here that, in endothelial cells, human A1 is rapidly inducible by phorbol ester and the inflammatory cytokines, tumor necrosis factor-α and interleukin-1β, but not by the growth factors, basic fibroblast growth factor or vascular endothelial growth factor. A1 is the only known Bcl-2 family member that is inducible by inflammatory cytokines, suggesting that it may play a protective role during inflammation. Additionally, vascular smooth muscle cells and various nonhematopoietic tissues express human A1, indicating that human A1 is a widely expressed Bcl-2 homologue.