文章基本信息

标题：Insulin-dependent diabetes induced by pancreatic beta cell expression of IL-15 and IL-15Rα
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作者：Jing Chen ; Lionel Feigenbaum ; Parirokh Awasthi 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2013
卷号：110
期号：33
页码：13534-13539
DOI：10.1073/pnas.1312911110
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Increased serum levels of IL-15 are reported in type 1 diabetes (T1D). Here we report elevated serum soluble IL-15R levels in human T1D. To investigate the role of IL-15/IL-15R in the pathogenesis of T1D, we generated double transgenic mice with pancreatic {beta}-cell expression of IL-15 and IL-15R. The mice developed hyperglycemia, marked mononuclear cell infiltration, {beta}-cell destruction, and anti-insulin autoantibodies that mimic early human T1D. The diabetes in this model was reversed by inhibiting IL-15 signaling with anti-IL2/IL15R{beta} (anti-CD122), which blocks IL-15 transpresentation. Furthermore, the diabetes could be reversed by administration of the Janus kinase 2/3 inhibitor tofacitinib, which blocks IL-15 signaling. In an alternative diabetes model, nonobese diabetic mice, IL15/IL-15R expression was increased in islet cells in the prediabetic stage, and inhibition of IL-15 signaling with anti-CD122 at the prediabetic stage delayed diabetes development. In support of the view that these observations reflect the conditions in humans, we demonstrated pancreatic islet expression of both IL-15 and IL-15R in human T1D. Taken together our data suggest that disordered IL-15 and IL-15R may be involved in T1D pathogenesis and the IL-15/IL15R system and its signaling pathway may be rational therapeutic targets for early T1D.