Suarez-Pinzon W L, Strynadka K, Schulz R, Rabinovitch A
Department of Medicine, University of Alberta, Edmonton, Canada.
Endocrinology. 1994 Mar;134(3):1006-10. doi: 10.1210/endo.134.3.8119136.
Cytokines produced by immune system cells infiltrating pancreatic islets are candidate mediators of islet beta-cell destruction in insulin-dependent diabetes mellitus. In this study, we examined the role of nitric oxide (NO) as a mediator of cytokine-induced islet beta-cell destruction in a rat insulinoma cell line (RINm5F). The cytokine combination of interleukin-1 beta (IL-1 beta; 10 U/ml), tumor necrosis factor-alpha (10(3) U/ml), and interferon-gamma (10(3) U/ml) induced DNA fragmentation (first detected at 6 h), mitochondrial damage (by 12 h), and death (by 24 h) of RIN cells, whereas the individual cytokines did not have these destructive effects. Also, the cytokine combination of IL-1 beta, tumor necrosis factor-alpha, and interferon-gamma induced a 10-fold increase in NO production by RIN cells, and L-NG-monomethyl arginine, an inhibitor of NO synthase, produced a dose-dependent inhibition of cytokine-induced NO production, DNA fragmentation, and cell destruction. However, IL-1 beta, acting alone, induced a 7-fold increase in NO production without causing DNA fragmentation, mitochondrial damage, or cell destruction. In addition, nicotinamide, a known inhibitor of ADP ribosylation and scavenger of oxygen free radicals, inhibited cytokine-induced DNA fragmentation and cell destruction without affecting NO production. We conclude that stimulation of NO production may be a necessary, but not sufficient, condition for cytokine-induced destruction of islet beta-cells.
浸润胰岛的免疫系统细胞产生的细胞因子是胰岛素依赖型糖尿病中胰岛β细胞破坏的潜在介质。在本研究中，我们在大鼠胰岛素瘤细胞系（RINm5F）中研究了一氧化氮（NO）作为细胞因子诱导的胰岛β细胞破坏介质的作用。白细胞介素-1β（IL-1β；10 U/ml）、肿瘤坏死因子-α（10³ U/ml）和干扰素-γ（10³ U/ml）的细胞因子组合诱导RIN细胞出现DNA片段化（6小时首次检测到）、线粒体损伤（12小时）和死亡（24小时），而单一细胞因子没有这些破坏作用。此外，IL-1β、肿瘤坏死因子-α和干扰素-γ的细胞因子组合使RIN细胞的NO产生增加了10倍，NO合酶抑制剂L-NG-单甲基精氨酸对细胞因子诱导的NO产生、DNA片段化和细胞破坏产生剂量依赖性抑制。然而，单独作用的IL-1β使NO产生增加了7倍，但未引起DNA片段化、线粒体损伤或细胞破坏。此外，烟酰胺是一种已知的ADP核糖基化抑制剂和氧自由基清除剂，它抑制细胞因子诱导的DNA片段化和细胞破坏，但不影响NO产生。我们得出结论，刺激NO产生可能是细胞因子诱导胰岛β细胞破坏的必要但不充分条件。
