期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 112, 期 43, 页码 E5815-E5824出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1509627112
关键词
endothelium; immunology; inflammation; lymphocytes; transplantation
资金
- British Heart Foundation [FS/11/64/28945]
- National Institutes of Health Research
- British Heart Foundation [FS/12/38/29640, FS/11/64/28945] Funding Source: researchfish
- Versus Arthritis [19791] Funding Source: researchfish
Constitutive resistance to cell death induced by inflammatory stimuli activating the extrinsic pathway of apoptosis is a key feature of vascular endothelial cells (ECs). Although this property is central to the maintenance of the endothelial barrier during inflammation, the molecular mechanisms of EC protection from cell-extrinsic, proapoptotic stimuli have not been investigated. We show that the Ig-family member CD31, which is expressed by endothelial but not epithelial cells, is necessary to prevent EC death induced by TNF-alpha and cytotoxic T lymphocytes in vitro. Combined quantitative RT-PCR array and biochemical analysis show that, upon the engagement of the TNF receptor with TNF-alpha on ECs, CD31 becomes activated and, in turn, counteracts the proapoptotic transcriptional program induced by TNF-alpha via activation of the Erk/Akt pathway. Specifically, Akt activation by CD31 signals prevents the localization of the forkhead transcription factor FoxO3 to the nucleus, thus inhibiting transcription of the proapoptotic genes CD95/Fas and caspase 7 and de-repressing the expression of the antiapoptotic gene cFlar. Both CD31 intracellular immunoreceptor tyrosine-based inhibition motifs are required for its prosurvival function. In vivo, CD31 gene transfer is sufficient to recapitulate the cytoprotective mechanisms in CD31(-) pancreatic beta cells, which become resistant to immune-mediated rejection when grafted in fully allogeneic recipients.
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