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 Szabo, Alex Rabinovitch

Research output: Contribution to journalArticle

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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
StatePublished - 2001
Externally publishedYes

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Peroxynitrous Acid
Islets of Langerhans
Cytokines
Nitric Oxide
Hydrogen Peroxide
Interleukin-1
Superoxides
Tumor Necrosis Factor-alpha
omega-N-Methylarginine
Nitric Oxide Synthase Type II
Oxidants
Nitric Oxide Synthase
Interferons
Pancreas
Reactive Oxygen Species
3-nitrotyrosine

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

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

Peroxynitrite is a mediator of cytokine-induced destruction of human pancreatic islet β cells. / Lakey, Jonathan R T; Suarez-Pinzon, Wilma L.; Strynadka, Ken; Korbutt, Gregory S.; Rajotte, Ray V.; Mabley, Jon G.; Szabo, Csaba; Rabinovitch, Alex.

In: Laboratory Investigation, Vol. 81, No. 12, 2001, p. 1683-1692.

Research output: Contribution to journalArticle

Lakey, JRT, Suarez-Pinzon, WL, Strynadka, K, Korbutt, GS, Rajotte, RV, Mabley, JG, Szabo, C & Rabinovitch, A 2001, 'Peroxynitrite is a mediator of cytokine-induced destruction of human pancreatic islet β cells', Laboratory Investigation, vol. 81, no. 12, pp. 1683-1692.
Lakey JRT, Suarez-Pinzon WL, Strynadka K, Korbutt GS, Rajotte RV, Mabley JG et al. Peroxynitrite is a mediator of cytokine-induced destruction of human pancreatic islet β cells. Laboratory Investigation. 2001;81(12):1683-1692.
Lakey, Jonathan R T ; Suarez-Pinzon, Wilma L. ; Strynadka, Ken ; Korbutt, Gregory S. ; Rajotte, Ray V. ; Mabley, Jon G. ; Szabo, Csaba ; Rabinovitch, Alex. / Peroxynitrite is a mediator of cytokine-induced destruction of human pancreatic islet β cells. In: Laboratory Investigation. 2001 ; Vol. 81, No. 12. pp. 1683-1692.
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AU - Rajotte, Ray V.

AU - Mabley, Jon G.

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AU - Rabinovitch, Alex

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