Nuclear Factor (NF)-κB–regulated X-chromosome–linked <i>iap</i> Gene Expression Protects Endothelial Cells from Tumor Necrosis Factor α–induced Apoptosis

TLDR

iap genes protect cells from apoptotic death in response to various stimuli. The study shows that NF‑κB–induced upregulation of the X‑chromosome–linked iap gene protects endothelial cells from TNF‑α–induced apoptosis, and that inhibition of NF‑κB or loss of iap expression increases cell death.

Abstract

By differential screening of tumor necrosis factor α (TNF-α) 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-α, interleukin 1β, and LPS, reagents that lead to activation of the nuclear transcription factor κB (NF-κB). Indeed, overexpression of IκBα, an inhibitor of NF-κB, suppresses the induced expression of iap genes and sensitizes ECs to TNF-α–induced apoptosis. Ectopic expression of one member of the human iap genes, human X-chromosome–linked iap (xiap), using recombinant adenovirus overrules the IκBα effect and protects ECs from TNF-α– induced apoptosis. We conclude that xiap represents one of the NF-κB–regulated genes that counteracts the apoptotic signals caused by TNF-α and thereby prevents ECs from undergoing apoptosis during inflammation.