Rabinovitch A, Suarez-Pinzon W L, Strynadka K, Lakey J R, Rajotte R V
Department of Medicine, University of Alberta, Edmonton, Canada.
J Clin Endocrinol Metab. 1996 Sep;81(9):3197-202. doi: 10.1210/jcem.81.9.8784069.
Cytokines produced by immune system cells infiltrating pancreatic islets are candidate mediators of islet beta-cell destruction in autoimmune insulin-dependent diabetes mellitus. Cytokine-induced islet beta-cell destruction may be mediated by reactive oxygen intermediates. To determine the possible roles of oxygen free radicals and nitric oxide (NO) as mediators of islet beta-cell destruction, we studied the relationships among cytokine-induced beta-cell destruction, production of malondialdehyde (MDA; an end product of lipid peroxidation), and production of nitrite (the stable end product of NO). The cytokine combination of interleukin-1 beta (50 U/mL), tumor necrosis factor-alpha (10(3) U/mL), and interferon-gamma (10(3) U/mL) induced significant increases in MDA and nitrite and significant decreases in insulin and DNA in islets after 60-h incubation. A novel antioxidant (lazaroid U78518E) significantly inhibited both a strong oxidant. t-butylhydroperoxide, and the combination of cytokines from inducing MDA production, but not from increasing nitrite production in the islets. Also, the lazaroid antioxidant significantly reversed the cytokine-induced decreases in insulin and DNA contents of the islet cultures. In contrast, L-NG-monomethyl arginine, an inhibitor of NO synthase, prevented cytokine-induced nitrite production, but did not prevent cytokine-induced increases in MDA and decreases in insulin and DNA in the islet cultures. In addition, the addition of MDA to the islets produced a dose-dependent decrease in their insulin and DNA contents, and this was only partially prevented by the lazaroid antioxidant. These results suggest that cytokines may be toxic to human islet beta-cells by inducing oxygen free radicals, lipid peroxidation, and aldehyde production in the islets, and that MDA is one of the cytotoxic mediators of cytokine-induced beta-cell destruction.
浸润胰岛的免疫系统细胞产生的细胞因子是自身免疫性胰岛素依赖型糖尿病中胰岛β细胞破坏的潜在介质。细胞因子诱导的胰岛β细胞破坏可能由活性氧中间体介导。为了确定氧自由基和一氧化氮（NO）作为胰岛β细胞破坏介质的可能作用，我们研究了细胞因子诱导的β细胞破坏、丙二醛（MDA；脂质过氧化的终产物）的产生与亚硝酸盐（NO的稳定终产物）的产生之间的关系。白细胞介素-1β（50 U/mL）、肿瘤坏死因子-α（10³ U/mL）和干扰素-γ（10³ U/mL）的细胞因子组合在孵育60小时后可导致胰岛中MDA和亚硝酸盐显著增加，胰岛素和DNA显著减少。一种新型抗氧化剂（拉扎罗类化合物U78518E）可显著抑制强氧化剂叔丁基过氧化氢以及细胞因子组合诱导胰岛产生MDA，但不能抑制其增加亚硝酸盐的产生。此外，拉扎罗类抗氧化剂可显著逆转细胞因子诱导的胰岛培养物中胰岛素和DNA含量的降低。相比之下，NO合酶抑制剂L-NG-单甲基精氨酸可阻止细胞因子诱导的亚硝酸盐产生，但不能阻止细胞因子诱导的胰岛培养物中MDA增加以及胰岛素和DNA减少。此外，向胰岛中添加MDA会使其胰岛素和DNA含量呈剂量依赖性降低，而拉扎罗类抗氧化剂只能部分阻止这种降低。这些结果表明，细胞因子可能通过诱导胰岛中的氧自由基、脂质过氧化和醛类产生而对人胰岛β细胞有毒性作用，并且MDA是细胞因子诱导的β细胞破坏的细胞毒性介质之一。
