Studies on autodestructive cytokine production by pancreatic beta-cells

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Interleukin-1 (IL-1) induced tumor necrosis factor-alpha (TNF-alpha) mRNA expression and bioactive TNF-alpha production by mouse islet cells. Hydrocortisone and nicotinamide suppressed the IL-1-induced TNF-alpha mRNA expression and TNF-alpha production. The agents attenuated the damage of islet cells exposed to IL-1. Whereas neither cyclosporin nor FK506 inhibited the TNF-alpha production by islet cells.Interferon-gamma (IFN-gamma) and TNF-alpha synergistically induced nitric oxide (NO) synthase mRNA expression and NO generation by mouse islet cells. The NO production was inhibited by nicotinamide. Incubation of islet cells with an NO donor nitroprusside resulted in the activation of poly (ADP-ribose) synthetase and the reduction of intracellular NAD content. The NAD reduction and poly (ADP-ribose) synthesis were inhibited by a poly (ADP-ribose) synthestase inhibitor 3-aminobenzamide.These observations suggest that islet cell damage in type 1 diabetes may be attributable to NO generation by islet cells induced by cytokines released by infiltrating mononuclear cells and endogenous cytokines produced by islet endocrine cells. The cytokine-induced islet cell damage and streptozotocin- or alloxan-induced islet cell destruction may have a common mechanism.