Mechanisms of β-cell death in response to double-stranded (ds) RNA and interferon-γ -: dsRNA-dependent protein kinase apoptosis and nitric oxide-dependent necrosis
Mechanisms of β-cell death in response to double-stranded (ds) RNA and interferon-γ -: dsRNA-dependent protein kinase apoptosis and nitric oxide-dependent necrosis
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DOI：
10.1016/s0002-9440(10)61693-8
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发表时间：
2001-07-01
影响因子：
6
通讯作者：
Corbett, JA
中科院分区：
文献类型：
--
作者：
Scarim, AL;Arnush, M;Corbett, JA
病毒感染是一种环境因素，其被认为是可能在糖尿病发展期间引发β细胞损伤的促发事件。本研究检查了病毒复制中间体双链（ds）RNA损害β细胞功能并诱导β细胞死亡的机制。合成的dsRNA分子聚肌苷酸-聚胞苷酸（polyIC）刺激β细胞DNA损伤和凋亡而不损害胰岛分泌功能。相反，聚IC和干扰素（IFN）-γ的组合刺激胰岛细胞的DNA损伤、凋亡和坏死，并且这种损伤与葡萄糖刺激的胰岛素分泌的抑制相关。一氧化氮介导多聚IC + IFN-γ对胰岛素分泌和胰岛细胞坏死的抑制和破坏作用。一氧化氮合酶、氨基胍和N-G-单甲基-L-精氨酸的抑制剂将聚IC + IFN-γ诱导的DNA损伤减弱至单独对聚IC应答时观察到的水平，防止胰岛细胞坏死，并防止对葡萄糖刺激的胰岛素分泌的抑制作用。N-G-单甲基-L-精氨酸不能阻止poly IC-和poly IC + IFN-γ诱导的胰岛细胞凋亡。PKR是介导感染细胞中抗病毒反应的dsRNA依赖性蛋白激酶，是poly IC和poly IC + IFN-γ诱导的胰岛细胞凋亡所需的，但不是一氧化氮介导的胰岛细胞坏死所需的。单独的多聚IC不能刺激从PKR缺陷小鼠分离的胰岛中的DNA损伤;然而，由多聚IC + IFN-γ的组合诱导的一氧化氮依赖性DNA损伤不会因PKR的遗传缺失而减弱。这些发现表明，dsRNA刺激PKR依赖性胰岛细胞凋亡，这是一个与正常相关的事件。胰岛分泌功能相反，多聚IC + IFN-γ诱导的葡萄糖刺激的胰岛素分泌抑制和胰岛细胞坏死是由胰岛产生一氧化氮介导的事件。这些发现表明至少一种IFN-γ诱导的抗病毒应答（胰岛细胞坏死）是通过PKR非依赖性途径介导的。
Viral infection is one environmental factor that has been implicated as a precipitating event that may initiate beta -cell damage during the development of diabetes. This study examines the mechanisms by which the viral replicative Intermediate, double-stranded (ds) RNA impairs beta -cell function and induces beta -cell death. The synthetic dsRNA molecule polyinosinic-polycytidylic acid (poly IC) stimulates beta -cell DNA damage and apoptosis without impairing islet secretory function. In contrast, the combination of poly IC and interferon (IFN)-gamma stimulates DNA damage, apoptosis, and necrosis of islet cells, and this damage is associated with the inhibition of glucose-stimulated Insulin secretion. Nitric oxide mediates the inhibitory and destructive actions of poly IC + IFN-gamma on insulin secretion and islet cell necrosis. Inhibitors of nitric oxide synthase, aminoguanidine, and N-G-monomethyl-L-arginine, attenuate poly IC + IFN-gamma -induced DNA damage to levels observed in response to poly IC alone, prevent islet cell necrosis, and prevent the inhibitory actions on glucose-stimulated insulin secretion. N-G-monomethyl-L-arginine fails to prevent poly IC- and poly IC + IFN-gamma -induced islet cell apoptosis. PKR, the dsRNA-dependent protein kinase that mediates the antiviral response in infected cells, is required for poly IC- and poly IC + IFN-gamma -induced islet cell apoptosis, but not nitric oxide-mediated islet cell necrosis. Alone, poly IC fails to stimulate DNA damage in islets isolated from PKR-deficient mice; however, nitric oxide-dependent DNA damage Induced by the combination of poly IC + IFN-gamma is not attenuated by the genetic absence of PKR. These findings indicate that dsRNA stimulates PKR-dependent islet cell apoptosis, an event that is associated with normal. islet secretory function. In contrast, poly IC + IFN-gamma -induced inhibition of glucose-stimulated insulin secretion and islet cell necrosis are events that are mediated by islet production of nitric oxide. These findings suggest that at least one IFN-gamma -induced anti-viral response (islet cell necrosis) is mediated through a PKR-Independent pathway.