Essential role for signal transducer and activator of transcription-1 in pancreatic β-cell death and autoimmune type 1 diabetes of nonobese diabetic mice

Abstract

OBJECTIVE - We have reported important roles for signal transducer and activator of transcription-1 (STAT1) in pancreatic β-cell death by cytokines in vitro. However, in vivo evidence supporting the role for STAT1 in natural type 1 diabetes has not been reported. We studied whether STAT1 plays an important role in the development of natural type 1 diabetes. RESEARCH DESIGN AND METHODS - We produced nonobese diabetic (NOD)/STAT1-/- mice by backcrossing and studied the in vivo role of STAT1 in β-cell death and type 1 diabetes. RESULTS - STAT1-/- islet cells were resistant to death by interferon (IFN)-γ/tumor necrosis factor (TNF)-α or IFN-γ/interleukin (IL)-1β combination. Cytochrome c translocation by IFN-γ/TNF-α was abrogated in STAT1-/- islet cells. The induction of X-linked inhibitor of apoptosis protein by TNF-α was inhibited by IFN-γ in STAT1+/- islet cells but not in STAT1-/- islet cells. Inducible nitric oxide (NO) synthase induction and NO production by IFN-γ/IL-1β were impaired in STAT1-/- islet cells. Strikingly, diabetes and insulitis were completely abrogated in NOD/STAT1-/- mice. Development of diabetes after CD4+ diabetogenic T-cell transfer was inhibited in those mice. STAT1-/- neonatal pancreata were not destroyed when grafted into diabetic NOD/BDC2.5 mice that developed CD4+ T-cell-dependent islet cell death. In NOD/STAT1-/- mice, autoreactive T-cell priming was not impaired, but Th1 differentiation was impaired. A janus kinase (JAK) 2 inhibitor upstream of STAT1 attenuated islet cell death by IFN-γ/TNF-α or IFN-γ/IL-1β and delayed diabetes onset in NOD/BDC2.5-SCID mice. CONCLUSIONS - These data demonstrate a critical role for STAT1 in β-cell death, T-cell immunoregulation, and type 1 diabetes in vivo and suggest potential therapeutic values of STAT1 or JAK inhibitors in the treatment/prevention of type 1 diabetes. © 2007 by the American Diabetes Association.