Studies on autodestructive cytokine production by pancreatic beta-cells

白细胞介素-1 （IL-1）诱导小鼠胰岛细胞肿瘤坏死因子- α (tnf - α) mRNA表达和生物活性tnf - α的产生。氢化可的松和烟酰胺抑制il -1诱导的tnf - α mRNA表达和tnf - α的产生。这些药物减轻了暴露于IL-1的胰岛细胞的损伤。而环孢素和FK506均不能抑制胰岛细胞产生tnf - α。干扰素- γ (ifn - γ)和tnf - α协同诱导小鼠胰岛细胞一氧化氮（NO）合成酶mRNA表达和NO生成。烟酰胺对NO的产生有抑制作用。用一氧化氮供体硝普苷孵育胰岛细胞可激活聚腺苷核糖合成酶，降低细胞内NAD含量。聚adp -核糖合成酶抑制剂3-氨基苯酰胺抑制NAD还原和聚adp -核糖合成。这些观察结果表明，1型糖尿病的胰岛细胞损伤可能是由于浸润性单核细胞释放的细胞因子和胰岛内分泌细胞产生的内源性细胞因子诱导胰岛细胞产生NO。细胞因子诱导的胰岛细胞损伤与链脲佐菌素或四氧嘧啶诱导的胰岛细胞破坏可能具有共同的机制。

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.