Corbett J A, Wang J L, Misko T P, Zhao W, Hickey W F, McDaniel M L
Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110.
Autoimmunity. 1993;15(2):145-53. doi: 10.3109/08916939309043889.
Nitric oxide has recently been implicated as a cellular molecule that mediates interleukin-1 beta (IL-1 beta)-induced inhibition of glucose-stimulated insulin secretion by islets of Langerhans. In this study evidence is presented which demonstrates that islets contain both the cytokine inducible and the constitutive isoforms of nitric oxide synthase as determined by NADPH diaphorase staining and immunohistochemical localization. Untreated islets contain NADPH diaphorase activity, and the intensity of NADPH diaphorase staining is dramatically increased after culture for 18 hrs with IL-1 beta. Both control and IL-1 beta-induced NADPH diaphorase staining of islets is inhibited by the nitric oxide synthase inhibitor NG-monomethyl-L-arginine (NMMA). Importantly, approximately 60-70% of islet cells stained positive for NADPH diaphorase (under both IL-1 beta treated and control conditions), suggesting that a subset of islet cells contain nitric oxide synthase. The beta-cell appears to be the endocrine cell type which contains constitutive nitric oxide synthase as demonstrated by immunohistochemical co-localization of constitutive nitric oxide synthase and insulin. IL-1 beta is believed to stimulate the expression of cytokine inducible nitric oxide synthase because the synthetic glucocorticoid, dexamethasone, prevents IL-1 beta induced inhibition of glucose stimulated insulin secretion and cGMP accumulation by islets. Both dexamethasone, and the nitric oxide synthase inhibitors NMMA and aminoguanidine also prevent IL-1 beta induced islet degeneration. These results indicate that nitric oxide produced by the inducible isoform of nitric oxide synthase mediates cytokine induced islet dysfunction and destruction, and that the beta-cell is the islet endocrine cellular source of constitutive nitric oxide synthase.
一氧化氮最近被认为是一种细胞分子，它介导白细胞介素-1β（IL-1β）诱导的胰岛对葡萄糖刺激的胰岛素分泌的抑制作用。在本研究中，通过NADPH黄递酶染色和免疫组织化学定位证明，胰岛同时含有细胞因子诱导型和组成型一氧化氮合酶同工型。未经处理的胰岛含有NADPH黄递酶活性，用IL-1β培养18小时后，NADPH黄递酶染色强度显著增加。一氧化氮合酶抑制剂NG-单甲基-L-精氨酸（NMMA）可抑制胰岛的对照和IL-1β诱导的NADPH黄递酶染色。重要的是，大约60-70%的胰岛细胞NADPH黄递酶染色呈阳性（在IL-1β处理和对照条件下均如此），这表明胰岛细胞的一个亚群含有一氧化氮合酶。免疫组织化学共定位组成型一氧化氮合酶和胰岛素表明，β细胞似乎是含有组成型一氧化氮合酶的内分泌细胞类型。据信IL-1β刺激细胞因子诱导型一氧化氮合酶的表达，因为合成糖皮质激素地塞米松可防止IL-1β诱导的胰岛对葡萄糖刺激的胰岛素分泌的抑制作用以及cGMP的积累。地塞米松以及一氧化氮合酶抑制剂NMMA和氨基胍也可防止IL-1β诱导的胰岛退变。这些结果表明，一氧化氮合酶诱导型产生的一氧化氮介导细胞因子诱导的胰岛功能障碍和破坏，并且β细胞是组成型一氧化氮合酶的胰岛内分泌细胞来源。
