title: Role of nitric oxide in the pathogenesis of encephalomyocarditis virus-induced diabetes in mice.
abstract: The D variant of encephalomyocarditis virus (EMC-D virus) causes diabetes in mice by destroying pancreatic beta cells. In mice infected with a low dose of EMC-D virus, macrophages play an important role in beta-cell destruction by producing soluble mediators such as interleukin-1beta (IL-1beta), tumor necrosis factor alpha (TNF-alpha), and nitric oxide (NO). To investigate the role of NO and inducible NO synthase (iNOS) in the development of diabetes in EMC-D virus-infected mice, we infected iNOS-deficient DBA/2 mice with EMC-D virus (2 x 10(2) PFU/mouse). Mean blood glucose levels in EMC-D virus-infected iNOS-deficient mice and wild-type mice were 205.5 and 466.7 mg/dl, respectively. Insulitis and macrophage infiltration were reduced in islets of iNOS-deficient mice compared with wild-type mice at 3 days after EMC-D virus infection. Apoptosis of beta cells was decreased in iNOS-deficient mice, as evidenced by reduced numbers of terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling-positive cells. There were no differences in mRNA expression of antiapoptotic molecules Bcl-2, Bcl-xL, Bcl-w, Mcl-1, cIAP-1, and cIAP-2 between wild-type and iNOS-deficient mice, whereas expression of proapoptotic Bax and Bak mRNAs was significantly decreased in iNOS-deficient mice. Expression of IL-1beta and TNF-alpha mRNAs was significantly decreased in both islets and macrophages of iNOS-deficient mice compared with wild-type mice after EMC-D virus infection. Nuclear factor kappaB was less activated in macrophages of iNOS-deficient mice after virus infection. We conclude that NO plays an important role in the activation of macrophages and apoptosis of pancreatic beta cells in EMC-D virus-infected mice and that deficient iNOS gene expression inhibits macrophage activation and beta-cell apoptosis, contributing to prevention of EMC-D virus-induced diabetes.
authors.affiliation: Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, Yeonsu-ku, Incheon, South Korea.
authors.forename: Young-Sun
authors.initials: YS
authors.lastname: Lee
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.forename: Seungjin
authors.initials: S
authors.lastname: Shin
authors.forename: Hee-Sook
authors.initials: HS
authors.lastname: Jun
mesh_terms: D000818:Animals; D017209:Apoptosis; D001786:Blood Glucose; D018188:Cardiovirus Infections / Q000276:immunology / Q000503:physiopathology / Q000821:virology*; D002478:Cells, Cultured; D003920:Diabetes Mellitus / Q000276:immunology / Q000503:physiopathology / Q000821:virology*; D004195:Disease Models, Animal; D004686:Encephalomyocarditis virus / Q000276:immunology / Q000472:pathogenicity* / Q000502:physiology; D005260:Female; D006801:Humans; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000821:virology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D016328:NF-kappa B / Q000276:immunology; D009569:Nitric Oxide / Q000276:immunology*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000276:immunology
chemical_list: D001786:Blood Glucose; D016328:NF-kappa B; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II