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Insulin-dependent diabetes induced by pancreatic beta cell expression of IL-15 and IL-15R?.

ABSTRACT: 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 ?-cell expression of IL-15 and IL-15R?. The mice developed hyperglycemia, marked mononuclear cell infiltration, ?-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? (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.

SUBMITTER: Chen J

PROVIDER: S-EPMC3746870 | biostudies-other | 2013 Aug

REPOSITORIES: biostudies-other

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Insulin-dependent diabetes induced by pancreatic beta cell expression of IL-15 and IL-15Rα.

Chen Jing J Feigenbaum Lionel L Awasthi Parirokh P Butcher Donna O DO Anver Miriam R MR Golubeva Yelena G YG Bamford Richard R Zhang Xiaojie X St Claire Mark B MB Thomas Craig J CJ Discepolo Valentina V Jabri Bana B Waldmann Thomas A TA

Proceedings of the National Academy of Sciences of the United States of America 20130731 33

Increased serum levels of IL-15 are reported in type 1 diabetes (T1D). Here we report elevated serum soluble IL-15Rα levels in human T1D. To investigate the role of IL-15/IL-15Rα in the pathogenesis of T1D, we generated double transgenic mice with pancreatic β-cell expression of IL-15 and IL-15Rα. The mice developed hyperglycemia, marked mononuclear cell infiltration, β-cell destruction, and anti-insulin autoantibodies that mimic early human T1D. The diabetes in this model was reversed by inhibi ...[more]

PMID: 23904478

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Dataset Information

Insulin-dependent diabetes induced by pancreatic beta cell expression of IL-15 and IL-15R?.

Publications

Insulin-dependent diabetes induced by pancreatic beta cell expression of IL-15 and IL-15Rα.

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