HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Online-Only Appendix All Versions of this Article: db06-1372v1 56/10/2561    most recent Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Kim, S. Articles by Lee, M.-S. Search for Related Content PubMed PubMed Citation Articles by Kim, S. Articles by Lee, M.-S. Social Bookmarking                What's this?

Essential Role for Signal Transducer and Activator of Transcription-1 in Pancreatic ß-Cell Death and Autoimmune Type 1 Diabetes of Nonobese Diabetic Mice

¹ Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
² Department of Biotechnology, Daegu University, Kyungsan, Kyungbuk, Korea
³ Department of Life Science, Gwangju Institute of Science and Technology, Gwangju, Korea

Address correspondence and reprint requests to Myung-Shik Lee, Department of Medicine, Samsung Medical Center, 50 Irwon-dong Kangnam-ku, Seoul 135-710, Korea. E-mail: mslee{at}smc.samsung.co.kr

Abbreviations: CFSE, 5,6-carboxylfluorescein diacetate succinimidyl ester; CTLA-4, cytotoxic T-cell antigen 4; EAE, experimental allergic encephalomyelitis; IFN, interferon; IL, interleukin; JAK, janus kinase; MLN, mesenteric lymph nodes; MTT, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide; PLN, pancreatic lymph nodes; STAT1, signal transducer and activator of transcription-1; TNF, tumor necrosis factor; XIAP, X-linked inhibitor of apoptosis

OBJECTIVE—We have reported important roles for signal transducer and activator of transcription-1 (STAT1) in pancreatic ß-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 ß-cell death and type 1 diabetes.

RESULTS—STAT1^–/– islet cells were resistant to death by interferon (IFN)-/tumor necrosis factor (TNF)- or IFN-/interleukin (IL)-1ß combination. Cytochrome c translocation by IFN-/TNF- was abrogated in STAT1^–/– islet cells. The induction of X-linked inhibitor of apoptosis protein by TNF- was inhibited by IFN- in STAT1^+/– islet cells but not in STAT1^–/– islet cells. Inducible nitric oxide (NO) synthase induction and NO production by IFN-/IL-1ß 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-/TNF- or IFN-/IL-1ß and delayed diabetes onset in NOD/BDC2.5-SCID mice.

CONCLUSIONS—These data demonstrate a critical role for STAT1 in ß-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.

CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?