Essential role for signal transducer and activator of transcription-1 in pancreatic β-cell death and autoimmune type 1 diabetes of nonobese diabetic mice
Essential role for signal transducer and activator of transcription-1 in pancreatic β-cell death and autoimmune type 1 diabetes of nonobese diabetic mice
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DOI：
10.2337/db06-1372
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发表时间：
2007-10-01
期刊：
影响因子：
7.7
通讯作者：
Lee, Myung-Shik
中科院分区：
文献类型：
--
作者：
Kim, Sunshin;Kim, Hun Sik;Lee, Myung-Shik
目的：我们报道了信号转导和转录激活因子L(STAT1)在体外细胞因子诱导的胰腺P细胞死亡中的重要作用。然而，目前还没有活体证据支持STAT1在自然1型糖尿病中的作用。研究设计与方法：采用回交方法建立非肥胖糖尿病(NOD)/STAT1(-/-)小鼠，研究STAT1在体内P细胞死亡和1型糖尿病中的作用。结果STAT1(-/-)胰岛细胞可通过干扰素(IFN)-γ/肿瘤坏死因子(TNN-α)或干扰素-γ/白介素1(IL)-1β的组合抵抗死亡。在STAT1(-/-)胰岛细胞中，干扰素-γ/肿瘤坏死因子-α诱导的细胞色素c转位被取消。干扰素-γ可抑制STAT1(+/-)胰岛细胞对肿瘤坏死因子-α诱导的X连锁凋亡抑制蛋白的表达，但对STAT1(-/-)胰岛细胞无明显影响。在STAT1(-/-)胰岛细胞中，诱导型一氧化氮合酶(NO)的诱导和由干扰素-γ/IL-1β产生的NO受到损害。令人惊讶的是，NOD/STAT1(-/-)小鼠的糖尿病和胰岛素炎完全被消除。在这些小鼠中，CD4(+)糖尿病T细胞转移后的糖尿病发展受到抑制。将STAT1(-/-)新生胰腺移植到出现CD4(+)T细胞依赖性胰岛细胞死亡的糖尿病NOD/BDC2.5小鼠体内，并未被破坏。在NOD/STAT1(-/-)小鼠中，自身反应性T细胞启动没有受损，但Th1分化受损。Janus Kinase(JAK)2抑制剂位于STAT1的上游。在NOD/BDC2.5-SCID小鼠中，这些数据表明STAT1在体内的β细胞死亡、T细胞免疫调节和1型糖尿病中起关键作用，并提示STAT1或JAK抑制剂在1型糖尿病的治疗/预防中的潜在治疗价值。
OBJECTIVE-We have reported important roles for signal transducer and activator of transcription-l (STAT1) in pancreatic P-cell death by cytokines in vitro. However, in vivo evidence supporting the role for STAT1 in natural type 1 diabetes has not been reported. We studied whether STAT1 plays an important role in the development of natural type 1 diabetes.RESEARCH DESIGN AND METHODS-We produced nonobese diabetic (NOD)/STAT1(-/-) mice by backcrossing and studied the in vivo role of STAT1 in P-cell death and type 1 diabetes.RESULTS-STAT1(-/-) islet cells were resistant to death by interferon (IFN)-gamma/tumor necrosis factor (TNn-alpha or IFN-gamma/interleukin (IL)-1 beta combination. Cytochrome c translocation by IFN-gamma/TNF-alpha was abrogated in STAT1(-/-) islet cells. The induction of X-linked inhibitor of apoptosis protein by TNF-alpha was inhibited by IFN-gamma in STAT1(+/-) islet cells but not in STAT1(-/-) islet cells. Inducible nitric oxide (NO) synthase induction and NO production by IFN-gamma/IL-1 beta were impaired in STAT1(-/-) islet cells. Strikingly, diabetes and insulitis were completely abrogated in NOD/STAT1(-/-) mice. Development of diabetes after CD4(+) diabetogenic T-cell transfer was inhibited in those mice. STAT1(-/-) neonatal pancreata were not destroyed when grafted into diabetic NOD/BDC2.5 mice that developed CD4(+) T-cell- dependent islet cell death. In NOD/STAT1(-/-) mice, autoreactive T-cell priming was not impaired, but Th1 differentiation was impaired. A janus kinase (JAK) 2 inhibitor upstream of STAT1. attenuated islet cell death by IFN-gamma/TNF-alpha or IFN-gamma/IL-1 beta and delayed diabetes onset in NOD/BDC2.5-SCID mice.CONCLUSIONS-These data demonstrate a critical role for STAT1 in beta-cell death, T-cell immunoregulation, and type 1 diabetes in vivo and suggest potential therapeutic values of STAT1 or JAK inhibitors in the treatment/prevention of type 1 diabetes.