1. A20 protects endothelial cells from TNF-, Fas-, and NK-mediated cell death by inhibiting caspase 8 activation
- Author
-
Jerome Mahiou, Soizic Daniel, Tala Shukri, Maria B. Arvelo, David W. Sun, Shane T. Grey, Christiane Ferran, Christopher R. Longo, Virendra I. Patel, Gautam V. Shrikhande, and Christina Mottley
- Subjects
Programmed cell death ,Hot Temperature ,Swine ,Fas-Associated Death Domain Protein ,Immunology ,Gene Expression ,Apoptosis ,Caspase 3 ,Caspase 6 ,Caspase 8 ,Biochemistry ,Necrosis ,immune system diseases ,hemic and lymphatic diseases ,Animals ,Humans ,fas Receptor ,Cycloheximide ,Cells, Cultured ,Tumor Necrosis Factor alpha-Induced Protein 3 ,Caspase ,Adaptor Proteins, Signal Transducing ,biology ,Tumor Necrosis Factor-alpha ,Intracellular Signaling Peptides and Proteins ,NF-kappa B ,Endothelial Cells ,Nuclear Proteins ,Proteins ,Complement System Proteins ,Cell Biology ,Hematology ,Fas receptor ,Caspase Inhibitors ,Mitochondria ,Cell biology ,DNA-Binding Proteins ,Enzyme Activation ,Killer Cells, Natural ,Caspases ,biology.protein ,Cattle ,Tumor necrosis factor alpha ,Signal Transduction - Abstract
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–κB (NF-κB). 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.
- Published
- 2004