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. 2011 Aug;89(8):785-98.
doi: 10.1007/s00109-011-0747-1. Epub 2011 Apr 13.

Cytokine Toxicity in Insulin-Producing Cells Is Mediated by Nitro-Oxidative Stress-Induced Hydroxyl Radical Formation in Mitochondria

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Cytokine Toxicity in Insulin-Producing Cells Is Mediated by Nitro-Oxidative Stress-Induced Hydroxyl Radical Formation in Mitochondria

Ewa Gurgul-Convey et al. J Mol Med (Berl). .

Abstract

Although nitric oxide (NO) and oxidative stress both contribute to proinflammatory cytokine toxicity in pancreatic β-cells during type 1 diabetes mellitus (T1DM) development, the interactions between NO and reactive oxygen species (ROS) in cytokine-mediated β-cell death have not been clarified. Exposure of insulin-producing RINm5F cells to IL-1β generated NO, while exposure to a combination of IL-1β, TNF-α, and IFN-γ, which simulates T1DM conditions, generated both NO and ROS. In theory, two reactions between NO and ROS are possible, one with the superoxide radical yielding peroxynitrite, and the other with hydrogen peroxide (H(2)O(2)) yielding hydroxyl radicals. Results of the present work exclude peroxynitrite involvement in cytokine toxicity to β-cells because its generation did not correlate with the toxic action of cytokines. On the other hand, we show that H(2)O(2), produced upon exposure of insulin-producing cell clones and primary rat islet cells to cytokines almost exclusively in the mitochondria, reacted in the presence of trace metal (Fe(++)) with NO forming highly toxic hydroxyl radicals, thus explaining the severe toxicity that causes apoptotic β-cell death. Expression of the H(2)O(2)-inactivating enzyme catalase in mitochondria protected against cytokine toxicity by preventing hydroxyl radical formation. We therefore conclude that proinflammatory cytokine-mediated β-cell death is due to nitro-oxidative stress-mediated hydroxyl radical formation in the mitochondria.

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