Corbett J A, Sweetland M A, Lancaster J R, McDaniel M L
Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110.
FASEB J. 1993 Feb 1;7(2):369-74. doi: 10.1096/fasebj.7.2.8440413.
Nitric oxide has been implicated as the effector molecule that mediates interleukin-1 beta (IL-1 beta)-induced inhibition of glucose-stimulated insulin secretion by rat islets. Brief exposures of islets (1 h) to IL-1 beta have been shown to inhibit glucose-stimulated insulin secretion at 8 or 18 h after removal of this cytokine. The purpose of this investigation was to determine if brief exposures of islets to IL-1 beta are sufficient to induce the formation of nitric oxide and to examine the signaling process associated with IL-1 beta-induced expression of nitric oxide synthase. We demonstrate that a 1-h pretreatment of islets with IL-1 beta followed by an 8-h incubation in the absence of this cytokine results in inhibition of glucose-stimulated insulin secretion (50%), which is completely prevented by pretreatment of islets with the nitric oxide synthase inhibitor NG-monomethyl-L-arginine (NMMA). The production of nitric oxide by islets under these pulse conditions is demonstrated by IL-1 beta-induced nitrite and electron paramagnetic resonance-detectable iron-nitrosyl complex formation, both of which are prevented by NMMA. IL-1 beta initiates a signal transduction process resulting in the expression of nitric oxide synthase. The signaling process appears to require the activation of a tyrosine kinase, since the tyrosine kinase inhibitor genistein prevents both IL-1 beta-induced inhibition of insulin secretion by islets and formation of nitric oxide by the insulinoma cell line RINm5F. These results show that short exposures of islets to IL-1 beta are sufficient to induce the formation of nitric oxide resulting in inhibition of glucose-stimulated insulin secretion and that a tyrosine kinase may participate in the early signaling events required for IL-1 beta to induce the expression of nitric oxide synthase.
一氧化氮被认为是介导白细胞介素-1β（IL-1β）诱导大鼠胰岛葡萄糖刺激的胰岛素分泌受抑制的效应分子。已表明胰岛短暂暴露于IL-1β（1小时）会在去除该细胞因子后的8小时或18小时抑制葡萄糖刺激的胰岛素分泌。本研究的目的是确定胰岛短暂暴露于IL-1β是否足以诱导一氧化氮的形成，并检查与IL-1β诱导的一氧化氮合酶表达相关的信号传导过程。我们证明，用IL-1β对胰岛进行1小时预处理，然后在不存在该细胞因子的情况下孵育8小时，会导致葡萄糖刺激的胰岛素分泌受到抑制（50%），而一氧化氮合酶抑制剂NG-单甲基-L-精氨酸（NMMA）对胰岛的预处理可完全防止这种抑制。在这些脉冲条件下，胰岛产生的一氧化氮通过IL-1β诱导的亚硝酸盐和电子顺磁共振可检测的铁-亚硝基络合物的形成得以证明，而这两者都可被NMMA阻止。IL-1β启动一个信号转导过程，导致一氧化氮合酶的表达。该信号传导过程似乎需要酪氨酸激酶的激活，因为酪氨酸激酶抑制剂染料木黄酮可防止IL-1β诱导胰岛对胰岛素分泌的抑制以及胰岛素瘤细胞系RINm5F产生一氧化氮。这些结果表明，胰岛短暂暴露于IL-1β足以诱导一氧化氮的形成，从而导致葡萄糖刺激的胰岛素分泌受到抑制，并且酪氨酸激酶可能参与IL-1β诱导一氧化氮合酶表达所需的早期信号事件。
