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.
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.
Authors: Maria Cecilia S Freitas; Yoichiro Uchida; Danyun Zhao; Bibo Ke; Ronald W Busuttil; Jerzy W Kupiec-Weglinski Journal: Liver Transpl Date: 2010-05 Impact factor: 5.799
Authors: Susan J Burke; Danhong Lu; Tim E Sparer; Thomas Masi; Matthew R Goff; Michael D Karlstad; J Jason Collier Journal: Am J Physiol Endocrinol Metab Date: 2013-11-26 Impact factor: 4.310
Authors: Danny Hung-Chieh Chou; Amedeo Vetere; Amit Choudhary; Stephen S Scully; Monica Schenone; Alicia Tang; Rachel Gomez; Sean M Burns; Morten Lundh; Tamara Vital; Eamon Comer; Patrick W Faloon; Vlado Dančík; Christie Ciarlo; Joshiawa Paulk; Mingji Dai; Clark Reddy; Hanshi Sun; Matthew Young; Nicholas Donato; Jacob Jaffe; Paul A Clemons; Michelle Palmer; Steven A Carr; Stuart L Schreiber; Bridget K Wagner Journal: J Am Chem Soc Date: 2015-06-15 Impact factor: 15.419
Authors: Susan J Burke; Barrett L Updegraff; Rachel M Bellich; Matthew R Goff; Danhong Lu; Steven C Minkin; Michael D Karlstad; J Jason Collier Journal: Mol Endocrinol Date: 2013-09-06
Authors: Qiwen Shen; Ken M Riedl; Rachel M Cole; Christopher Lehman; Lu Xu; Hansjuerg Alder; Martha A Belury; Steven J Schwartz; Ouliana Ziouzenkova Journal: J Agric Food Chem Date: 2015-02-12 Impact factor: 5.279