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Blood, 15 October 2004, Vol. 104, No. 8, pp. 2376-2384. Prepublished online as a Blood First Edition Paper on July 13, 2004; DOI 10.1182/blood-2003-02-0635. This Article Full Text (PDF) All Versions of this Article: 2003-02-0635v1 104/8/2376    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Daniel, S. Articles by Ferran, C. Search for Related Content PubMed PubMed Citation Articles by Daniel, S. Articles by Ferran, C. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted February 27, 2003 Accepted June 30, 2004 A20 protects endothelial cells from TNF, FAS and NK mediated cell death by inhibiting caspase 8 activation Soizic Daniel, Maria B Arvelo, Virendra I Patel, Christopher R Longo, Gautam Shrikhande, Tala Shukri, Jerome Mahiou, David W Sun, Christina Mothley, Shane T Grey, and Christiane Ferran* Department of Surgery and Medicine, Immunobiology Research Center and Division of Vascular Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA Division of Immunology, Beth Israel Deaconess Medical Center , Harvard Medical School, Boston, MA, USA Arthritis and Inflammation, The Garvan Institute of Medical Research, Dar Linghurst, Australia * Corresponding author; email: cferran{at}caregroup.harvard.edu. A20 is a stress response gene in endothelial cells (EC). A20 serves a dual cytoprotective function, protecting from TNF mediated apoptosis and inhibiting inflammation via blockade of the transcription factor NF-B. 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 and significantly blunts natural killer cells mediated EC apoptosis by inhibiting caspase 8 activation. In addition to protecting EC from apoptotic stimuli, A20 safeguards EC from complement-mediated necrosis. These data demonstrate, for the first time, that the cytoprotective effect of A20 in EC 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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