A20 protects endothelial cells from TNF-, Fas-, and NK-mediated cell death by inhibiting caspase 8 activation.

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-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.

journal_name

Blood

journal_title

Blood

authors

Daniel S,Arvelo MB,Patel VI,Longo CR,Shrikhande G,Shukri T,Mahiou J,Sun DW,Mottley C,Grey ST,Ferran C

doi

10.1182/blood-2003-02-0635

subject

Has Abstract

pub_date

2004-10-15 00:00:00

pages

2376-84

issue

8

eissn

0006-4971

issn

1528-0020

pii

2003-02-0635

journal_volume

104

pub_type

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