Nuclear Factor (NF)-kappa B-regulated X-chromosome-linked iap Gene Expression Protects Endothelial Cells from Tumor Necrosis Factor alpha -induced Apoptosis

doi:10.1084/jem.188.1.211

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J. Exp. Med., Volume 188, Number 1, July 1, 1998 211-216

Nuclear Factor (NF)- $kappa$ B-regulated X-chromosome-linked iap Gene Expression Protects Endothelial Cells from Tumor Necrosis Factor $alpha$ -induced Apoptosis

By Christian Stehlik, Rainer de Martin, Ichiro Kumabashiri, Johannes A. Schmid, Bernd R. Binder, and Joachim Lipp

From the Department of Vascular Biology and Thrombosis Research, Vienna International Research and Cooperation Center/University of Vienna, A-1235 Vienna, Austria

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 memberof the inhibitor of apoptosis (iap) gene family. iap genes functionto protect cells from undergoing apoptotic death in response toa variety of stimuli. These iap genes, hiap1, hiap2, and xiapwere found to be strongly upregulated upon treatment of ECs withthe inflammatory cytokines TNF- $alpha$ , interleukin 1 $beta$ , and LPS, reagentsthat 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 sensitizesECs to TNF- $alpha$ -induced apoptosis. Ectopic expression of one memberof the human iap genes, human X-chromosome-linked iap (xiap),using recombinant adenovirus overrules the I $kappa$ B $alpha$ effect and protectsECs from TNF- $alpha$ - induced apoptosis. We conclude that xiap representsone of the NF- $kappa$ B-regulated genes that counteracts the apoptoticsignals caused by TNF- $alpha$ and thereby prevents ECs from undergoingapoptosis during inflammation.

Key words: activation; inhibitor of apoptosis gene family; endothelial cells; adenovirus; nuclear factor $kappa$ B

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Nuclear Factor (NF)-B-regulated X-chromosome-linked iap Gene Expression Protects Endothelial Cells from Tumor Necrosis Factor -induced Apoptosis

Nuclear Factor (NF)- $kappa$ B-regulated X-chromosome-linked iap Gene Expression Protects Endothelial Cells from Tumor Necrosis Factor $alpha$ -induced Apoptosis