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Journal of Virology, August 2009, p. 8004-8011, Vol. 83, No. 16
0022-538X/09/$08.00+0     doi:10.1128/JVI.00205-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Role of Nitric Oxide in the Pathogenesis of Encephalomyocarditis Virus-Induced Diabetes in Mice{triangledown}

Young-Sun Lee,1 Na Li,2 Seungjin Shin,2 and Hee-Sook Jun1*

Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, Yeonsu-ku, Incheon, South Korea,1 Department of Pathology, Chicago Medical School, Rosalind Franklin University of Medicine, North Chicago, Illinois2

Received 28 January 2009/ Accepted 22 May 2009

The D variant of encephalomyocarditis virus (EMC-D virus) causes diabetes in mice by destroying pancreatic β cells. In mice infected with a low dose of EMC-D virus, macrophages play an important role in β-cell destruction by producing soluble mediators such as interleukin-1β (IL-1β), 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 102 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 β 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-1β 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 {kappa}B 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 β cells in EMC-D virus-infected mice and that deficient iNOS gene expression inhibits macrophage activation and β-cell apoptosis, contributing to prevention of EMC-D virus-induced diabetes.

* Corresponding author. Mailing address: Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, 7-45 Sondo-dong, Yeonsu-ku, Incheon 406-840, South Korea. Phone: 11-82-32-899-6056. Fax: 11-82-32-899-6057. E-mail: hsjeon{at}gachon.ac.kr

{triangledown} Published ahead of print on 17 June 2009.

Journal of Virology, August 2009, p. 8004-8011, Vol. 83, No. 16
0022-538X/09/$08.00+0     doi:10.1128/JVI.00205-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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