Peroxynitrite Is a Mediator of Cytokine-Induced Destruction of Human Pancreatic Islet β Cells

Abstract

The proinflammatory cytokines, interleukin-1β (IL-1β), tumor necrosis factor α (TNFα), and interferon γ (IFNγ), are cytotoxic to pancreatic islet β cells, possibly by inducing nitric oxide and/or oxygen radical production in the β 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 β-cell destruction. To test this hypothesis we incubated islets isolated from human pancreata with the cytokine combination of IL-1β, TNFα, and IFNγ. We found that these cytokines induced significant increases in nitrotyrosine, a marker of peroxynitrite, in islet β cells, and the increase in nitrotyrosine preceded islet-cell destruction. Peroxynitrite mimicked the effects of cytokines on nitrotyrosine formation and islet β-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 β-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 β-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 β cells.

DOI: 10.1038/labinvest.3780381
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@article{Lakey2001PeroxynitriteIA, title={Peroxynitrite Is a Mediator of Cytokine-Induced Destruction of Human Pancreatic Islet β Cells}, author={Jonathan R. T. Lakey and Wilma L. Suarez-Pinzon and Ken Strynadka and Gregory S. Korbutt and Ray V. Rajotte and J . G . Mabley and Csaba Szab{\'o} and A. Rabinovitch}, journal={Laboratory Investigation}, year={2001}, volume={81}, pages={1683-1692} }