Kwon G, Corbett J A, McDaniel M L
Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110-8118, USA.
Endocrinology. 1996 Mar;137(3):825-30. doi: 10.1210/endo.137.3.8603591.
Recent evidence indicates that nitric oxide (NO) produced after expression of inducible NO synthase (iNOS) mediates cytokine-induced inhibition of insulin secretion by pancreatic islets. The current studies were designed to characterize the involvement of immediate-early response genes, c-fos and c-jun, in interleukin 1 (IL-1)-induced expression of iNOS. iNOS messenger RNA (mRNA) expression by both rat islets and RINm5F cells was time dependent, with maximal expression observed after an approximately 3- to 6-h exposure to IL-1. IL-1 also stimulated rapid and transient expression of c-fos and c-jun by both rat islets and RINm5F cells, with maximal mRNA accumulation detected 30-60 min after IL-1 treatment. IL-1-induced protein synthesis of Fos and Jun was observed as early as 30 min, peaked between 3-5 h, and decreased by 8 h after IL-1 treatment. Temporal correlation of Fos and Jun expression and iNOS gene induction suggested that Fos and Jun might regulate iNOS gene transcription by rodent pancreatic beta-cells. The present study, however, indicates that IL-1 induced expression of Fos and Jun does not seem to participate in the regulation of iNOS and mRNA expression, because: 1) cycloheximide (1 microM) completely inhibited Fos expression but had no inhibitory effect on iNOS mRNA levels; and 2) tyrosine kinase inhibitors genistein and herbimycin A completely inhibited IL-1 induced iNOS expression but did not block c-fos and c-jun expression. These results indicate that two separate signaling pathways may exist for induction of c-fos and c- jun and iNOS genes and that de novo synthesis of Fos and Jun does not participate in the regulation of iNOS gene expression.
最近有证据表明，诱导型一氧化氮合酶（iNOS）表达后产生的一氧化氮（NO）介导细胞因子诱导的胰岛胰岛素分泌抑制。当前的研究旨在确定即刻早期反应基因c-fos和c-jun在白细胞介素1（IL-1）诱导的iNOS表达中的作用。大鼠胰岛和RINm5F细胞中iNOS信使核糖核酸（mRNA）的表达呈时间依赖性，在暴露于IL-1约3至6小时后观察到最大表达。IL-1还刺激大鼠胰岛和RINm5F细胞中c-fos和c-jun的快速和瞬时表达，在IL-1处理后30 - 60分钟检测到最大mRNA积累。早在30分钟就观察到IL-1诱导的Fos和Jun的蛋白质合成，在3 - 5小时达到峰值，并在IL-1处理后8小时下降。Fos和Jun表达与iNOS基因诱导的时间相关性表明，Fos和Jun可能通过啮齿动物胰腺β细胞调节iNOS基因转录。然而，本研究表明，IL-1诱导的Fos和Jun表达似乎不参与iNOS和mRNA表达的调节，原因如下：1）放线菌酮（1 microM）完全抑制Fos表达，但对iNOS mRNA水平没有抑制作用；2）酪氨酸激酶抑制剂染料木黄酮和除莠霉素A完全抑制IL-1诱导的iNOS表达，但不阻断c-fos和c-jun表达。这些结果表明，可能存在两条独立的信号通路来诱导c-fos和c-jun以及iNOS基因，并且Fos和Jun的从头合成不参与iNOS基因表达的调节。
