Cetkovic-Cvrlje M, Eizirik D L
Department of Medical Cell Biology, Uppsala University, Sweden.
Cytokine. 1994 Jul;6(4):399-406. doi: 10.1016/1043-4666(94)90064-7.
Cytokines may be important mediators of beta-cell damage in early insulin-dependent diabetes mellitus. In order to further characterize the mechanism(s) of action of cytokines on insulin-producing cells, mouse pancreatic islets were exposed for 48 h to IL-1 beta, IFN-gamma or TNF-alpha, alone or in combinations. The three cytokines induced islet nitric oxide (NO) production, an effect most marked when islets were exposed to the three cytokines together. In parallel with NO production, IL-1 beta+IFN-gamma+TNF-alpha impaired islet function, as judged by decreased islet DNA and insulin content, decreased glucose metabolism and decreased glucose-induced insulin release. Aminoguanidine, an inhibitor of NO production, prevented all the above described suppressive effects of the cytokines, with exception of depletion in islet insulin content. In parallel experiments, insulin-producing RIN cells were exposed for 6 h to the same cytokines. Both IL-1 beta and TNF-alpha, but not IFN-gamma, induced NO production and expression of the mRNA encoding for the inducible form of the enzyme NO synthase (iNOS). These effects were most pronounced when combinations of IL-1 beta+IFN-gamma or IL-1 beta+IFN-gamma+TNF-alpha were used. As a whole, the data suggest that combinations of cytokines induce higher amounts of NO generation by mouse pancreatic islets than each of the cytokines isolated. An important source of islet NO production are probably the beta-cells, as pointed by data obtained with an insulinoma cell line. Most of the deleterious effects of the cytokines of mouse islets are prevented by blocking NO production, suggesting that NO is the main mediator of cytokine-induced beta-cell damage.(ABSTRACT TRUNCATED AT 250 WORDS)
细胞因子可能是早期胰岛素依赖型糖尿病中β细胞损伤的重要介质。为了进一步阐明细胞因子对胰岛素分泌细胞的作用机制，将小鼠胰岛单独或联合暴露于白细胞介素-1β（IL-1β）、干扰素-γ（IFN-γ）或肿瘤坏死因子-α（TNF-α）48小时。这三种细胞因子均可诱导胰岛一氧化氮（NO）生成，当胰岛同时暴露于这三种细胞因子时，这种作用最为显著。与NO生成同时发生的是，IL-1β+IFN-γ+TNF-α损害胰岛功能，这可通过胰岛DNA和胰岛素含量降低、葡萄糖代谢减少以及葡萄糖诱导的胰岛素释放减少来判断。氨基胍是一种NO生成抑制剂，可预防细胞因子上述所有的抑制作用，但胰岛胰岛素含量的减少除外。在平行实验中，将胰岛素分泌的RIN细胞暴露于相同的细胞因子6小时。IL-1β和TNF-α均可诱导NO生成以及诱导型一氧化氮合酶（iNOS）编码mRNA的表达，但IFN-γ无此作用。当使用IL-1β+IFN-γ或IL-1β+IFN-γ+TNF-α组合时，这些作用最为明显。总体而言，数据表明细胞因子组合比单独的每种细胞因子诱导小鼠胰岛产生更多的NO。胰岛NO生成的一个重要来源可能是β细胞，胰岛素瘤细胞系获得的数据表明了这一点。通过阻断NO生成可预防细胞因子对小鼠胰岛的大多数有害作用，这表明NO是细胞因子诱导的β细胞损伤的主要介质。（摘要截短于250字）
