Peroxynitrite is a mediator of cytokine-induced destruction of human pancreatic islet beta cells

Lakey, J.R.T., Suarez-Pinzon, W.L., Strynadka, K., Korbutt, G.S., Rajotte, R., Mabley, J.G., Szabo, C. and Rabinovitch, A. (2001) Peroxynitrite is a mediator of cytokine-induced destruction of human pancreatic islet beta cells Laboratory Investigation, 81 (12). pp. 1683-1692. ISSN 0023-6837

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Abstract

The proinflammatory cytokines, interleukin-1beta (IL-1beta), tumor necrosis factor alpha (TNFalpha), and interferon gamma (IFNgamma), are cytotoxic to pancreatic islet beta cells, possibly by inducing nitric oxide and/or oxygen radical production in the beta cells. Peroxynitrite, the reaction product of nitric oxide and the superoxide radical, is a strong oxidant and cytotoxic mediator; therefore, we hypothesized that peroxynitrite might be a mediator of cytokine-induced islet beta-cell destruction. To test this hypothesis we incubated islets isolated from human pancreata with the cytokine combination of IL-1beta, TNFalpha, and IFNgamma. We found that these cytokines induced significant increases in nitrotyrosine, a marker of peroxynitrite, in islet beta cells, and the increase in nitrotyrosine preceded islet-cell destruction. Peroxynitrite mimicked the effects of cytokines on nitrotyrosine formation and islet beta-cell destruction. L-NG-monomethyl arginine, an inhibitor of nitric oxide synthase, prevented cytokine-induced nitric oxide production but not hydrogen peroxide production, nitrotyrosine formation, or islet beta-cell destruction. In contrast, guanidinoethyldisulphide, an inhibitor of inducible nitric oxide synthase and scavenger of peroxynitrite, prevented cytokine-induced nitric oxide and hydrogen peroxide production, nitrotyrosine formation, and islet beta-cell destruction. These results suggest that cytokine-induced peroxynitrite formation is dependent upon increased generation of superoxide (measured as hydrogen peroxide) and that peroxynitrite is a mediator of cytokine-induced destruction of human pancreatic islet beta cells.

Item Type: Journal article
Subjects: A000 Medicine > A900 Medicine not elsewhere classified
B000 Health Professions > B200 Pharmacology Toxicology and Pharmacy
DOI (a stable link to the resource): 10.1038/labinvest.3780381
Faculties: Faculty of Science and Engineering > School of Pharmacy and Biomolecular Sciences > Chemical Biology
Depositing User: editor spbs
Date Deposited: 21 Nov 2006
Last Modified: 07 Nov 2014 16:00
URI: http://eprints.brighton.ac.uk/id/eprint/209

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