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Cytokine-induced β-cell apoptosis is no-dependent, mitochondria-mediated and inhibited by bcl-xl

Holohan, C.
; 
Szegezdi, E.
; 
Ritter, T.
; 
O'Brien, T.
; 
Samali, A.
Identifiers
http://hdl.handle.net/10379/11970
https://doi.org/10.13025/26543
Repository DOI
10.1111/j.1582-4934.2007.00191.x
Publication Date
2008-04-01
Keywords
apoptosis, bcl-x-l, caspases, cytokines, inos, mitochondria, nitric oxide, type 1 diabetes, nitric-oxide synthase, endoplasmic-reticulum stress, cytochrome-c release, diabetes-mellitus, omi/htra2 protease, caspase activation, outer-membrane, kappa-b, death, induction
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Article
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Citation
Holohan, C. Szegezdi, E.; Ritter, T.; O'Brien, T.; Samali, A. (2008). Cytokine-induced β-cell apoptosis is no-dependent, mitochondria-mediated and inhibited by bcl-xl. Journal of Cellular and Molecular Medicine 12 (2), 591-606
Abstract
Pro-inflammatory cytokines are implicated as the main mediators of beta-cell death during type 1 diabetes but the exact mechanisms remain unknown. This study examined the effects of interleukin-1 beta (IL-1 beta), interferon-gamma (IFN gamma) and tumour necrosis factor alpha (TNF alpha) on a rat insulinoma cell line (RIN-r) in order to identify the core mechanism of cytokine-induced beta-cell death. Treatment of cells with a combination of IL-1 beta and IFN gamma (IL-1 beta/IFN gamma)-induced apoptotic cell death. TNF alpha neither induced beta-cell death nor did it potentiate the effects of IL-1 beta, IFN gamma or IL-1 beta/IFN gamma . The cytotoxic effect of IL-1 beta/IFN gamma was associated with the expression of inducible nitric oxide synthase (iNOS) and production of nitric oxide. Adenoviral-mediated expression of iNOS (AdiNOS) alone was sufficient to induce caspase activity and apoptosis. The broad range caspase inhibitor, Boc-D-fmk, blocked IL-1 beta/IFN gamma -induced caspase activity, but not nitric oxide production nor cell death. However, pre-treatment with L-NIO, a NOS inhibitor, prevented nitric oxide production, caspase activity and reduced apoptosis. IL-1 beta/IFN gamma -induced apoptosis was accompanied by loss of mitochondrial membrane potential, release of cytochrome c and cleavage of pro-caspase-9, -7 and -3. Transduction of cells with Ad-Bcl-X-L blocked both iNOS and cytokine-mediated mitochondrial changes and subsequent apoptosis, downstream of nitric oxide. We conclude that cytokine-induced nitric oxide production is both essential and sufficient for caspase activation and beta-cell death, and have identified Bcl-X-L as a potential target to combat beta-cell apoptosis.
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Publisher
Wiley-Blackwell
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Rights
Attribution-NonCommercial-NoDerivs 3.0 Ireland
cbn
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Externally hosted open access publications with University of Galway authors (2)