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MnSOD and Catalase Transgenes Demonstrate That Protection of Islets From Oxidative Stress Does Not Alter Cytokine Toxicity

¹ Department of Pediatrics, University of Louisville, Louisville, Kentucky
² Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky

Reactive oxygen species (ROS) and nitric oxide (NO) are proposed mediators of cytokine-induced ß-cell destruction in type 1 diabetes. We produced transgenic mice with increased ß-cell expression of manganese superoxide dismutase (MnSOD) and catalase. Expression of these antioxidants increased ß-cell ROS scavenging and improved ß-cell survival after treatment with different sources of ROS. MnSOD or catalase conferred protection against streptozotocin (STZ)-induced ß-cell injury. Coexpression of MnSOD and catalase provided synergistic protection against peroxynitrite and STZ. To determine the potential effect of these antioxidants on cytokine-induced toxicity, we exposed isolated islets to a cytokine mixture, including interleukin-1ß and interferon-. Cytokine toxicity was measured as reduced metabolic activity after 6 days and reduced insulin secretion after 1 day. Cytokines increased ROS production, and both antioxidants were effective in reducing cytokine-induced ROS. However, MnSOD and/or catalase provided no protection against cytokine-induced injury. To understand this, the nuclear factor-B (NF-B) signaling cascade was investigated. Antioxidants reduced NF-B activation by ROS, but none of the antioxidants altered activation by cytokines, as measured by inhibitor of B phosphorylation, NF-B translocation, inducible NO synthase activation, and NO production. Our data agree with previous reports that antioxidants benefit ß-cell survival against ROS damage, but they are not consistent with reports that antioxidants reduce cytokine toxicity. ROS appear to have no role in cytokine toxicity in primary ß-cells.

Abbreviations: 1400W, N-(3-(aminomethyl)enzyl)acetamidine; CM-H₂DCFDA, 5-(6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate; IFN-, interferon-; IB, inhibitor of B; IL-1ß, interleukin-1ß; iNOS, inducible NO synthase; L-NAME, N^G-nitro-L-arginine methyl ester; MnSOD, manganese superoxide dismutase; NF-B, nuclear factor B; ROS, reactive oxygen species; SIN-1, 3-morpholinosydnonimine; SOD, superoxide dismutase; STZ, streptozotocin

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