Stehlik C, de Martin R, Kumabashiri I, Schmid J A, Binder B R, Lipp J
Department of Vascular Biology and Thrombosis Research, Vienna International Research and Cooperation Center/University of Vienna, A-1235 Vienna, Austria.
J Exp Med. 1998 Jul 6;188(1):211-6. doi: 10.1084/jem.188.1.211.
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.
通过对肿瘤坏死因子α（TNF-α）和脂多糖（LPS）激活的内皮细胞（ECs）进行差异筛选，我们鉴定出一个cDNA克隆，结果表明它是凋亡抑制因子（iap）基因家族的成员。iap基因的功能是保护细胞免受各种刺激引发的凋亡死亡。在用炎性细胞因子TNF-α、白细胞介素1β和LPS处理ECs后，发现这些iap基因，即hiap1、hiap2和xiap被强烈上调，这些试剂可导致核转录因子κB（NF-κB）激活。事实上，NF-κB抑制剂IkappaBalpha的过表达可抑制iap基因的诱导表达，并使ECs对TNF-α诱导的凋亡敏感。使用重组腺病毒异位表达人类iap基因之一的人类X染色体连锁凋亡抑制蛋白（xiap），可消除IkappaBalpha的作用，并保护ECs免受TNF-α诱导的凋亡。我们得出结论，xiap代表NF-κB调节的基因之一，它可抵消TNF-α引起的凋亡信号，从而防止ECs在炎症过程中发生凋亡。
