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Proc Natl Acad Sci U S A. 2013 Aug 13;110(33):13534-9. doi: 10.1073/pnas.1312911110. Epub 2013 Jul 31.

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

Author information

1
Metabolism Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892-1374, USA.

Abstract

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 inhibiting IL-15 signaling with anti-IL2/IL15Rβ (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-15Rα 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-15Rα in human T1D. Taken together our data suggest that disordered IL-15 and IL-15Rα may be involved in T1D pathogenesis and the IL-15/IL15Rα system and its signaling pathway may be rational therapeutic targets for early T1D.

PMID:
23904478
PMCID:
PMC3746870
DOI:
10.1073/pnas.1312911110
[Indexed for MEDLINE]
Free PMC Article

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