Nuclear factor (NF)-κB-regulated X-chromosome-linked iap gene expression protects endothelial cells from tumor necrosis factor α-induced apoptosis

By differential screening of tumor necrosis factor alpha (TNF-alpha) and lipopolysaccharide (LPS)-activated endothelial cells (ECs), we have identified a cDNA clone that turned out to be a member of the inhibitor of apoptosis (iap) gene family. iap genes function to protect cells from undergoing apoptotic death in response to a variety of stimuli. These iap genes, hiap1, hiap2, and xiap were found to be strongly upregulated upon treatment of ECs with the inflammatory cytokines TNF-alpha, interleukin 1 beta, and LPS, reagents that lead to activation of the nuclear transcription factor kappa B (NF-kappa B). Indeed, overexpression of I kappa B alpha, an inhibitor of NF-kappa B, suppresses the induced expression of iap genes and sensitizes ECs to TNF-alpha-induced apoptosis. Ectopic expression of one member of the human iap genes, human X-chromosome-linked iap (xiap), using recombinant adenovirus overrules the I kappa B alpha effect and protects ECs from TNF-alpha-induced apoptosis. We conclude that xiap represents one of the NF-kappa B-regulated genes that counteracts the apoptotic signals caused by TNF-alpha and thereby prevents ECs from undergoing apoptosis during inflammation.