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Activated T-cells and macrophages infiltrate pancreatic islets early in the pathogenesis of type 1 diabetes. Their secretion of different pro- inflammatory cytokines such as interleukin (IL)-1β, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α affects [β-cell function. Here we report that a combination of these cytokines inhibits insulin release, stimulates inducible nitric oxide synthase (iNOS), and upregulates the surface expression of Fas in NIT-1 β-cells and intact mouse islets. Using iNOS- deficient and Fas-deficient islets, respectively, we investigated the relative contribution of NO and Fas upregulation in cytokine-induced β-cell damage. Interestingly, inhibition of insulin release did not occur in the absence of NO production. However, de novo expression of Fas-specific mRNA and Fas cell surface expression were detected and thus appear to be NO- independent. The lack of NO production partially protected islets from cytokine-induced apoptosis but had no effect on cell death induced by cell surface cross-linking of Fas with soluble Fas ligand (FasL). The absence of FasL on β-cells and the degree of apoptosis observed in Fas-deficient islets exclude the possibility of cytokine-induced fratricide. In conclusion, pro- inflammatory cytokines exert a cytotoxic effect on β-cells via an NO- dependent pathway and, in parallel, render β-cells susceptible to Fas:FasL- mediated, NO-independent cell death triggered by activated T-cells.

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Journal article



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39 - 47