Nuclear factor (NF)-kappaB-regulated X-chromosome-linked iap gene expression protects endothelial cells from tumor necrosis factor alpha-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 1beta, and LPS, reagents that lead to activation of the nuclear transcription factor kappaB (NF-kappaB). Indeed, overexpression of IkappaBalpha, an inhibitor of NF-kappaB, 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 IkappaBalpha effect and protects ECs from TNF-alpha- induced apoptosis. We conclude that xiap represents one of the NF-kappaB-regulated genes that counteracts the apoptotic signals caused by TNF-alpha and thereby prevents ECs from undergoing apoptosis during inflammation.
Stehlik
C
C
Department of Vascular Biology and Thrombosis Research, Vienna International Research and Cooperation Center/University of Vienna, A-1235 Vienna, Austria.
de Martin
R
R
Kumabashiri
I
I
Schmid
J A
JA
Binder
B R
BR
Lipp
J
J
D000256:Adenoviridae / Q000737:chemistry; D017209:Apoptosis / Q000502:physiology*; D002478:Cells, Cultured; D004247:DNA / Q000032:analysis; D053938:DNA Fragmentation / Q000235:genetics; D004730:Endothelium, Vascular / Q000378:metabolism; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000235:genetics*; D008040:Genetic Linkage / Q000235:genetics; D016328:NF-kappa B / Q000502:physiology*; D009363:Neoplasm Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014764:Viral Proteins / Q000502:physiology; D014960:X Chromosome / Q000235:genetics*
D016328:NF-kappa B; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D014764:Viral Proteins; C030193:immunosuppressive acidic protein; D004247:DNA