Corbett J A, Kwon G, Marino M H, Rodi C P, Sullivan P M, Turk J, McDaniel M L
Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Am J Physiol. 1996 Jun;270(6 Pt 1):C1581-7. doi: 10.1152/ajpcell.1996.270.6.C1581.
Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease that is characterized by selective destruction of insulin-secreting beta-cells. Cytokines have been implicated as effector molecules that participate in both islet inflammation and beta-cell destruction during the development of IDDM. In this study, the effects of cytokines on the expression of inducible nitric oxide synthase (iNOS) and inducible cyclooxygenase (COX-2) by human islets were examined. In combination, the cytokines, human recombinant interleukin-1 beta (IL-1 beta), human recombinant tumor necrosis factor-alpha (TNF-alpha), and human recombinant interferon-gamma (IFN-gamma), induce the time-dependent formation of nitrite and prostaglandin E2 (PGE2) by human islets. The nitric oxide synthase inhibitor NG-monomethyl-L-arginine (L-NMMA) completely inhibits cytokine-induced nitrite formation and attenuates PGE2 production by human islets. L-NMMA does not inhibit cytokine-induced expression of COX-2 by human islets, suggesting that nitric oxide may directly activate cyclooxygenase, an effect that has been previously demonstrated for isolated rat islets. This combination of cytokines (IL-1 beta, TNF-alpha, and IFN-gamma) also induces the expression of iNOS mRNA by human islets as demonstrated by both reverse transcriptase-polymerase chain reaction and Northern blot analysis. We further show that the tyrosine kinase inhibitors genistein and herbimycin A prevent IL-1 beta plus IFN-gamma-induced expression of COX-2 and iNOS and the production of PGE2 and nitric oxide by human islets. These results demonstrate that cytokines induce the expression of iNOS and COX-2 by human islets and that cytokine-induced expression of both COX-2 and iNOS by human islets appears to require the activation of a tyrosine kinase(s).
胰岛素依赖型糖尿病（IDDM）是一种自身免疫性疾病，其特征是胰岛素分泌β细胞被选择性破坏。细胞因子被认为是在IDDM发展过程中参与胰岛炎症和β细胞破坏的效应分子。在本研究中，检测了细胞因子对人胰岛诱导型一氧化氮合酶（iNOS）和诱导型环氧化酶（COX-2）表达的影响。细胞因子，人重组白细胞介素-1β（IL-1β）、人重组肿瘤坏死因子-α（TNF-α）和人重组干扰素-γ（IFN-γ）联合作用，可诱导人胰岛随时间形成亚硝酸盐和前列腺素E2（PGE2）。一氧化氮合酶抑制剂NG-单甲基-L-精氨酸（L-NMMA）完全抑制细胞因子诱导的亚硝酸盐形成，并减弱人胰岛PGE2的产生。L-NMMA不抑制细胞因子诱导的人胰岛COX-2表达，这表明一氧化氮可能直接激活环氧化酶，这一效应先前已在分离的大鼠胰岛中得到证实。逆转录聚合酶链反应和Northern印迹分析均表明，这种细胞因子组合（IL-1β、TNF-α和IFN-γ）也可诱导人胰岛iNOS mRNA的表达。我们进一步表明，酪氨酸激酶抑制剂染料木黄酮和赫司特霉素A可阻止IL-1β加IFN-γ诱导的人胰岛COX-2和iNOS表达以及PGE2和一氧化氮的产生。这些结果表明，细胞因子可诱导人胰岛iNOS和COX-2的表达，并且细胞因子诱导的人胰岛COX-2和iNOS表达似乎需要酪氨酸激酶的激活。
