| First Author | Chen J | Year | 2013 |
| Journal | Proc Natl Acad Sci U S A | Volume | 110 |
| Issue | 33 | Pages | 13534-9 |
| PubMed ID | 23904478 | Mgi Jnum | J:200680 |
| Mgi Id | MGI:5509081 | Doi | 10.1073/pnas.1312911110 |
| Citation | Chen J, et al. (2013) Insulin-dependent diabetes induced by pancreatic beta cell expression of IL-15 and IL-15Ralpha. Proc Natl Acad Sci U S A 110(33):13534-9 |
| abstractText | Increased serum levels of IL-15 are reported in type 1 diabetes (T1D). Here we report elevated serum soluble IL-15Ralpha levels in human T1D. To investigate the role of IL-15/IL-15Ralpha in the pathogenesis of T1D, we generated double transgenic mice with pancreatic beta-cell expression of IL-15 and IL-15Ralpha. 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/IL15Rbeta (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-15Ralpha 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-15Ralpha in human T1D. Taken together our data suggest that disordered IL-15 and IL-15Ralpha may be involved in T1D pathogenesis and the IL-15/IL15Ralpha system and its signaling pathway may be rational therapeutic targets for early T1D. |
