Islet-specific expression of IL-10 promotes diabetes in nonobese diabetic mice independent of Fas, perforin, TNF receptor-1, and TNF receptor-2 molecules
Islet-specific expression of IL-10 promotes diabetes in nonobese diabetic mice independent of Fas, perforin, TNF receptor-1, and TNF receptor-2 molecules
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DOI：
10.4049/jimmunol.165.5.2841
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发表时间：
2000-09-01
影响因子：
4.4
通讯作者：
Sarvetnick, N
中科院分区：
文献类型：
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作者：
Balasa, B;Van Gunst, K;Sarvetnick, N
几种死亡信号或死亡诱导分子与β细胞破坏有关，包括Fas、穿孔素和TNFR-1。在本研究中，我们检查了每种死亡信号分子在非肥胖糖尿病（NOD）小鼠的il -10加速糖尿病中的作用，各组IL-10-NOD小鼠，每组Fas、穿孔素或TNFR-1分子缺乏，容易发展成胰岛素炎。随后死于糖尿病，其动力学和发病率与野生型或杂合IL-10-NOD幼崽相似。同样，TNFR-2缺乏也不能阻断IL-10-NOD小鼠的加速糖尿病和NOD小鼠的自发性糖尿病。这些结果表明，胰腺IL-10促进糖尿病独立于Fas、穿孔素、TNFR-1和TNFR-2分子。随后，将糖尿病诱导剂环磷酰胺注射到无胰岛素的NOD中。Lpr / Lpr小鼠，这些小鼠都没有患上胰岛素或糖尿病。我们的数据表明，环磷酰胺（而非IL-10）诱导的糖尿病是Fas依赖性的。总的来说，这些发现提供了证据，表明胰腺中IL-10的表达促进糖尿病独立于主要的死亡途径，并为鉴定新的死亡途径提供了动力，这些死亡途径促使自身免疫破坏产生胰岛素的β细胞。
Several death-signaling or death-inducing molecules have been implicated in beta cell destruction, including Fas, perforin, and TNFR-1, In this study, we examined the role of each death-signaling molecule in the IL-10-accelerated diabetes of nonobese diabetic (NOD) mice, Groups of IL-10-NOD mice, each deficient in either Fas, perforin, or TNFR-1 molecules, readily developed insulitis, and subsequently succumbed to diabetes with an accelerated kinetics and incidence similar to that observed in their wild-type or heterozygous IL-10-NOD littermates. Similarly, a TNFR-2 deficiency did not block accelerated diabetes in IL-10-NOD mice and spontaneous diabetes In NOD mice. These results demonstrate that pancreatic IL-10 promotes diabetes independent of Fas, perforin, TNFR-1, and TNFR-2 molecules. Subsequently, when cyclophosphamide, a diabetes-inducing agent, was injected into insulitis-free NOD..lpr/lpr mice, none of these mice developed insulitis or diabetes. Our data suggest that cyclophosphamide-but not IL-10-induced diabetes is Fas dependent, Overall, these findings provide evidence that pancreatic expression of IL-10 promotes diabetes independent of the major death pathways and provide impetus for identification of novel death pathways precipitating autoimmune destruction of insulin-producing beta cells.