OBJECTIVE: Exposure of beta-cells to inflammatory cytokines leads to apoptotic cell death through the activation of gene networks under the control of specific transcription factors, such as interferon-gamma-induced signal transducer and activator of transcription (STAT)-1. We previously demonstrated that beta-cells lacking STAT-1 are resistant to cytokine-induced cell death in vitro. The aim of this study was to investigate the effect of STAT-1 elimination on immune-mediated beta-cell destruction in vivo. RESEARCH DESIGN AND METHODS: Multiple low-dose streptozotocin (STZ) was given to C57BL/6 mice after syngeneic STAT-1(-/-) or wild-type islet transplantation. STAT-1(-/-) and wild-type islets were also transplanted in alloxan-diabetic BALB/c and spontaneously diabetic nonobese diabetic (NOD) mice. Additionally, mice were treated with interleukin (IL)-1 blockade (IL-1 receptor antagonist [IL-1ra]) and low-dose T-cell suppression (cyclosporine A [CsA]). RESULTS: When exposed to multiple low-dose STZ in an immune-competent host, STAT-1(-/-) islets were more resistant to destruction than wild-type islets (28 vs. 100% diabetes incidence, P < or = 0.05). STAT-1 deletion also protected allogeneic islet grafts against primary nonfunction in autoimmune NOD mice (0 vs. 17% using wild-type islets). However, no difference in survival time was observed. Additionally, treating recipients with IL-1ra and CsA prolonged graft survival in chemically diabetic BALB/c mice, whereas no difference was seen between STAT-1(-/-) and C57BL/6 grafts. CONCLUSIONS: These data indicate that STAT-1 is a key player in immune-mediated early beta-cell dysfunction and death. When considering the many effector mechanisms contributing to beta-cell death following islet transplantation, multiple combined interventions will be needed for prolongation of beta-cell survival in the autoimmune context of type 1 diabetes.
OBJECTIVE: Exposure of beta-cells to inflammatory cytokines leads to apoptotic cell death through the activation of gene networks under the control of specific transcription factors, such as interferon-gamma-induced signal transducer and activator of transcription (STAT)-1. We previously demonstrated that beta-cells lacking STAT-1 are resistant to cytokine-induced cell death in vitro. The aim of this study was to investigate the effect of STAT-1 elimination on immune-mediated beta-cell destruction in vivo. RESEARCH DESIGN AND METHODS: Multiple low-dose streptozotocin (STZ) was given to C57BL/6 mice after syngeneic STAT-1(-/-) or wild-type islet transplantation. STAT-1(-/-) and wild-type islets were also transplanted in alloxan-diabetic BALB/c and spontaneously diabetic nonobese diabetic (NOD) mice. Additionally, mice were treated with interleukin (IL)-1 blockade (IL-1 receptor antagonist [IL-1ra]) and low-dose T-cell suppression (cyclosporine A [CsA]). RESULTS: When exposed to multiple low-dose STZ in an immune-competent host, STAT-1(-/-) islets were more resistant to destruction than wild-type islets (28 vs. 100% diabetes incidence, P < or = 0.05). STAT-1 deletion also protected allogeneic islet grafts against primary nonfunction in autoimmune NOD mice (0 vs. 17% using wild-type islets). However, no difference in survival time was observed. Additionally, treating recipients with IL-1ra and CsA prolonged graft survival in chemically diabetic BALB/c mice, whereas no difference was seen between STAT-1(-/-) and C57BL/6 grafts. CONCLUSIONS: These data indicate that STAT-1 is a key player in immune-mediated early beta-cell dysfunction and death. When considering the many effector mechanisms contributing to beta-cell death following islet transplantation, multiple combined interventions will be needed for prolongation of beta-cell survival in the autoimmune context of type 1 diabetes.
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: Lian Yi; Chia-Feng Tsai; Ercument Dirice; Adam C Swensen; Jing Chen; Tujin Shi; Marina A Gritsenko; Rosalie K Chu; Paul D Piehowski; Richard D Smith; Karin D Rodland; Mark A Atkinson; Clayton E Mathews; Rohit N Kulkarni; Tao Liu; Wei-Jun Qian Journal: Anal Chem Date: 2019-03-15 Impact factor: 6.986
Authors: C Gysemans; H Callewaert; F Moore; M Nelson-Holte; L Overbergh; D L Eizirik; C Mathieu Journal: Diabetologia Date: 2009-09-08 Impact factor: 10.122