| First Author | Kim S | Year | 2007 |
| Journal | Diabetes | Volume | 56 |
| Issue | 10 | Pages | 2561-8 |
| PubMed ID | 17620422 | Mgi Jnum | J:126568 |
| Mgi Id | MGI:3761584 | Doi | 10.2337/db06-1372 |
| Citation | Kim S, et al. (2007) Essential role for signal transducer and activator of transcription-1 in pancreatic beta-cell death and autoimmune type 1 diabetes of nonobese diabetic mice. Diabetes 56(10):2561-8 |
| abstractText | OBJECTIVE: We have reported important roles for signal transducer and activator of transcription-1 (STAT1) in pancreatic beta-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 beta-cell death and type 1 diabetes. RESULTS: STAT1(-/-) islet cells were resistant to death by interferon (IFN)-gamma/tumor necrosis factor (TNF)-alpha or IFN-gamma/interleukin (IL)-1 beta combination. Cytochrome c translocation by IFN-gamma/TNF-alpha was abrogated in STAT1(-/-) islet cells. The induction of X-linked inhibitor of apoptosis protein by TNF-alpha was inhibited by IFN-gamma in STAT1(+/-) islet cells but not in STAT1(-/-) islet cells. Inducible nitric oxide (NO) synthase induction and NO production by IFN-gamma/IL-1 beta 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-gamma/TNF-alpha or IFN-gamma/IL-1 beta and delayed diabetes onset in NOD/BDC2.5-SCID mice. CONCLUSIONS: These data demonstrate a critical role for STAT1 in beta-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. |
