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

Jonathan R.T. Lakey, Wilma L. Suarez-Pinzon, Ken Strynadka, Gregory S. Korbutt, Ray V. Rajotte, Jon G. Mabley, Csaba Szabó, Alex Rabinovitch

Research output: Contribution to journalArticlepeer-review

78 Scopus citations

Abstract

The proinflammatory cytokines, interleukin-1β (IL-1β), tumor necrosis factor α (TNFα), and interferon γ (IFN-γ), 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.

Original languageEnglish (US)
Pages (from-to)1683-1692
Number of pages10
JournalLaboratory Investigation
Volume81
Issue number12
DOIs
StatePublished - 2001
Externally publishedYes

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Cell Biology

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