Viral infection is one environmental factor that may contribute to the initiation of pancreatic β-cell destruction during the development of autoimmune diabetes. Picornaviruses, such as encephalomyocarditis virus (EMCV), induce a pro-inflammatory response in islets leading to local production of cytokines, such as IL-1, by resident islet leukocytes. Furthermore, IL-1 is known to stimulate β-cell expression of iNOS and production of the free radical nitric oxide. The purpose of this study was to determine whether nitric oxide contributes to the β-cell response to viral infection. We show that nitric oxide protects β-cells against virally mediated lysis by limiting EMCV replication. This protection requires low micromolar, or iNOS-derived, levels of nitric oxide. At these concentrations nitric oxide inhibits the Krebs enzyme aconitase and complex IV of the electron transport chain. Like nitric oxide, pharmacological inhibition of mitochondrial oxidative metabolism attenuates EMCV-mediated β-cell lysis by inhibiting viral replication. These findings provide novel evidence that cytokine signaling in β-cells functions to limit viral replication and subsequent β-cell lysis by attenuating mitochondrial oxidative metabolism in a nitric oxide–dependent manner.

中文翻译：

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抑制线粒体氧化代谢可减弱 EMCV 复制并保护 β 细胞免受病毒介导的裂解

病毒感染是一种环境因素，可能导致自身免疫性糖尿病发生过程中胰腺β细胞遭到破坏。小核糖核酸病毒，例如脑心肌炎病毒 (EMCV)，可在胰岛中诱导促炎反应，导致驻留胰岛白细胞局部产生细胞因子，例如 IL-1。此外，已知 IL-1 可以刺激 β 细胞表达 iNOS 并产生自由基一氧化氮。本研究的目的是确定一氧化氮是否有助于 β 细胞对病毒感染的反应。我们发现一氧化氮通过限制 EMCV 复制来保护 β 细胞免受病毒介导的裂解。这种保护需要低微摩尔或诱导一氧化氮合酶衍生的一氧化氮水平。在这些浓度下，一氧化氮会抑制克雷布斯酶乌头酸酶和电子传递链的复合物 IV。与一氧化氮一样，线粒体氧化代谢的药理学抑制通过抑制病毒复制来减弱 EMCV 介导的 β 细胞裂解。这些发现提供了新的证据，表明β细胞中的细胞因子信号传导通过以一氧化氮依赖性方式减弱线粒体氧化代谢来限制病毒复制和随后的β细胞裂解。