A20 protects endothelial cells from TNF-, Fas-, and NK-mediated cell death by inhibiting caspase 8 activation
A20 protects endothelial cells from TNF-, Fas-, and NK-mediated cell death by inhibiting caspase 8 activation
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DOI：
10.1182/blood-2003-02-0635
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发表时间：
2004-10-15
期刊：
影响因子：
20.3
通讯作者：
Ferran, C
中科院分区：
文献类型：
--
作者：
Daniel, S;Arvelo, MB;Ferran, C
A20是内皮细胞（EC）中的应激反应基因。A20具有双重细胞保护功能，通过阻断转录因子核因子-κ B（NF-κ B）来保护免受肿瘤坏死因子（TNF）介导的细胞凋亡和抑制炎症。在这项研究中，我们评估的细胞保护功能的A20在EC文化的分子基础，并质疑其保护作用是否超出TNF其他凋亡和坏死的刺激。我们的数据表明，A20通过抑制顶端半胱天冬酶8和2、执行者半胱天冬酶3和6的蛋白水解裂解、Bid裂解和细胞色素c的释放来靶向TNF凋亡途径，从而保持胞浆蛋白的完整性。A20还通过抑制半胱天冬酶8的活化，保护免于Fas/CD 95，并显著减弱自然杀伤细胞介导的EC凋亡。除了保护EC免受凋亡刺激外，A20还保护EC免受补体介导的坏死。这些数据首次证明，A20在EC中的细胞保护作用不限于TNF触发的细胞凋亡。相反，A20通过有效关闭由炎症和免疫罪犯引发的细胞死亡途径提供广泛的EC保护功能。(C)2004年，美国血液学会。
A20 is a stress response gene in endothelial cells (ECs). A20 serves a dual cytoprotective function, protecting from tumor necrosis factor (TNF)-mediated apoptosis and inhibiting inflammation via blockade of the transcription factor nuclear factor-kappaB (NF-kappaB). In this study, we evaluated the molecular basis of the cytoprotective function of A20 in EC cultures and questioned whether its protective effect extends beyond TNF to other apoptotic and necrotic stimuli. Our data demonstrate that A20 targets the TNF apoptotic pathway by inhibiting proteolytic cleavage of apical caspases 8 and 2, executioner caspases 3 and 6, Bid cleavage, and release of cytochrome c, thus preserving mitochondrion integrity. A20 also protects from Fas/CD95 and significantly blunts natural killer cell-mediated EC apoptosis by inhibiting caspase 8 activation. In addition to protecting ECs from apoptotic stimuli, A20 safeguards ECs from complement-mediated necrosis. These data demonstrate, for the first time, that the cytoprotective effect of A20 in ECs is not limited to TNF-triggered apoptosis. Rather, A20 affords broad EC protective functions by effectively shutting down cell death pathways initiated by inflammatory and immune offenders. (C) 2004 by The American Society of Hematology.