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

J.R.T. Lakey, W.L. Suarez-Pinzon, K. Strynadka, G.S. Korbutt, R. Rajotte, Jon Mabley, C. Szabo, A. Rabinovitch

Research output: Contribution to journalArticleResearchpeer-review

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.
Original languageEnglish
Pages (from-to)1683-1692
Number of pages10
JournalLaboratory Investigation
Volume81
Issue number12
DOIs
Publication statusPublished - 2001

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

Cite this

Lakey, J. R. T., Suarez-Pinzon, W. L., Strynadka, K., Korbutt, G. S., Rajotte, R., Mabley, J., ... Rabinovitch, A. (2001). Peroxynitrite is a mediator of cytokine-induced destruction of human pancreatic islet beta cells. Laboratory Investigation, 81(12), 1683-1692. https://doi.org/10.1038/labinvest.3780381
Lakey, J.R.T. ; Suarez-Pinzon, W.L. ; Strynadka, K. ; Korbutt, G.S. ; Rajotte, R. ; Mabley, Jon ; Szabo, C. ; Rabinovitch, A. / Peroxynitrite is a mediator of cytokine-induced destruction of human pancreatic islet beta cells. In: Laboratory Investigation. 2001 ; Vol. 81, No. 12. pp. 1683-1692.
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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.",
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Lakey, JRT, Suarez-Pinzon, WL, Strynadka, K, Korbutt, GS, Rajotte, R, Mabley, J, Szabo, C & Rabinovitch, A 2001, 'Peroxynitrite is a mediator of cytokine-induced destruction of human pancreatic islet beta cells', Laboratory Investigation, vol. 81, no. 12, pp. 1683-1692. https://doi.org/10.1038/labinvest.3780381

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, Jon; Szabo, C.; Rabinovitch, A.

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

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Peroxynitrite is a mediator of cytokine-induced destruction of human pancreatic islet beta cells

AU - Lakey, J.R.T.

AU - Suarez-Pinzon, W.L.

AU - Strynadka, K.

AU - Korbutt, G.S.

AU - Rajotte, R.

AU - Mabley, Jon

AU - Szabo, C.

AU - Rabinovitch, A.

PY - 2001

Y1 - 2001

N2 - 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.

AB - 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.

U2 - 10.1038/labinvest.3780381

DO - 10.1038/labinvest.3780381

M3 - Article

VL - 81

SP - 1683

EP - 1692

JO - Laboratory Investigation

JF - Laboratory Investigation

SN - 0023-6837

IS - 12

ER -