Do β-cells generate peroxynitrite in response to cytokine treatment? J Biol Chem 2013 Dec 20;288(51):36567-78
Date
11/07/2013Pubmed ID
24194521Pubmed Central ID
PMC3868769DOI
10.1074/jbc.M113.522243Scopus ID
2-s2.0-84890957625 (requires institutional sign-in at Scopus site) 23 CitationsAbstract
The purpose of this study was to determine the reactive species that is responsible for cytokine-mediated β-cell death. Inhibitors of inducible nitric oxide synthase prevent this death, and addition of exogenous nitric oxide using donors induces β-cell death. The reaction of nitric oxide with superoxide results in the generation of peroxynitrite, and this powerful oxidant has been suggested to be the mediator of β-cell death in response to cytokine treatment. Recently, coumarin-7-boronate has been developed as a probe for the selective detection of peroxynitrite. Using this reagent, we show that addition of the NADPH oxidase activator phorbol 12-myristate 13-acetate to nitric oxide-producing macrophages results in peroxynitrite generation. Using a similar approach, we demonstrate that cytokines fail to stimulate peroxynitrite generation by rat islets and insulinoma cells, either with or without phorbol 12-myristate 13-acetate treatment. When forced to produce superoxide using redox cyclers, this generation is associated with protection from nitric oxide toxicity. These findings indicate that: (i) nitric oxide is the likely mediator of the toxic effects of cytokines, (ii) β-cells do not produce peroxynitrite in response to cytokines, and (iii) when forced to produce superoxide, the scavenging of nitric oxide by superoxide is associated with protection of β-cells from nitric oxide-mediated toxicity.
Author List
Broniowska KA, Mathews CE, Corbett JAAuthor
John A. Corbett PhD Chair, Professor in the Biochemistry department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCell Death
Cell Line, Tumor
Insulin-Secreting Cells
Interferons
Macrophages
Male
Nitric Oxide
Nitric Oxide Synthase
Peroxynitrous Acid
Rats
Rats, Sprague-Dawley
Superoxides
Tetradecanoylphorbol Acetate
