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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Diabetes Mellitus, Type 1 / etiology*
  • Disease Models, Animal*
  • Humans
  • Insulin-Secreting Cells / metabolism*
  • Interleukin-15 / antagonists & inhibitors
  • Interleukin-15 / blood
  • Interleukin-15 / metabolism*
  • Interleukin-15 Receptor alpha Subunit / blood
  • Interleukin-15 Receptor alpha Subunit / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, Transgenic
  • Piperidines / pharmacology
  • Pyrimidines / pharmacology
  • Pyrroles / pharmacology
  • Signal Transduction / drug effects*

Substances

  • Interleukin-15
  • Interleukin-15 Receptor alpha Subunit
  • Piperidines
  • Pyrimidines
  • Pyrroles
  • tofacitinib