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


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.
Kim
Sunshin
S
Department of Medicine, Samsung Medical Center, 50 Irwon-dong Kangnam-ku, Seoul 135-710, Korea.
Kim
Hun Sik
HS
Chung
Kun Wook
KW
Oh
Seung Hoon
SH
Yun
Jong Won
JW
Im
Sin-Hyeog
SH
Lee
Moon-Kyu
MK
Kim
Kwang-Won
KW
Lee
Myung-Shik
MS
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000473:pathology*; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D050417:Insulin-Secreting Cells / Q000473:pathology*; D053612:Janus Kinases / Q000037:antagonists & inhibitors; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D050794:STAT1 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000502:physiology / Q000627:therapeutic use*
D004791:Enzyme Inhibitors; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D053612:Janus Kinases