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Journal of Virology, October 1999, p. 8541-8548, Vol. 73, No. 10
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Prevention of Encephalomyocarditis Virus-Induced Diabetes in Mice by Inhibition of the Tyrosine Kinase Signalling Pathway and Subsequent Suppression of Nitric Oxide Production in Macrophages

K. Hirasawa,1 H. S. Jun,1 H. S. Han,1 M. L. Zhang,1 M. D. Hollenberg,2 and J. W. Yoon1,3,*

Laboratory of Viral and Immunopathogenesis of Diabetes, Julia McFarlane Diabetes Research Centre, Department of Microbiology and Infectious Diseases,1 and Endocrine Research Group, Department of Pharmacology and Therapeutics, and Department of Medicine, Faculty of Medicine,2 University of Calgary, Calgary, Alberta, Canada, and Laboratory of Endocrinology, Institute for Medical Science, Department of Endocrinology and Metabolism, School of Medicine, Ajou University, Suwon, Korea3

Received 18 March 1999/Accepted 16 June 1999

Macrophages comprise the major population of cells infiltrating pancreatic islets during the early stages of infection in DBA/2 mice by the D variant of encephalomyocarditis virus (EMC-D virus). Inactivation of macrophages prior to viral infection almost completely prevents EMC-D virus-induced diabetes. This investigation was initiated to determine whether a tyrosine kinase signalling pathway might be involved in the activation of macrophages by EMC-D virus infection and whether tyrosine kinase inhibitors might, therefore, abrogate EMC-D virus-induced diabetes in vivo. When isolated macrophages were infected with EMC-D virus, inducible nitric oxide synthase mRNA was expressed and nitric oxide was subsequently produced. Treatment of macrophages with the tyrosine kinase inhibitor tyrphostin AG126, but not tyrphostin AG556, prior to EMC-D virus infection blocked the production of nitric oxide. The infection of macrophages with EMC-D virus also resulted in the activation of the mitogen-activated protein kinases (MAPKs) p42MAPK/ERK2/p44MAPK/ERK1, p38MAPK, and p46/p54JNK. In accord with the greater potency of AG126 than of AG556 in blocking EMC-D virus-mediated macrophage activation, the incidence of diabetes in EMC-D virus-infected mice treated with AG126 (25%) was much lower than that in AG556-treated (75%) or vehicle-treated (88%) control mice. We conclude that EMC-D virus-induced activation of macrophages resulting in macrophage-mediated beta -cell destruction can be prevented by the inhibition of a tyrosine kinase signalling pathway involved in macrophage activation.

* Corresponding author. Mailing address: Laboratory of Viral Immunopathogenesis of Diabetes, Julia McFarlane Diabetes Research Centre, Faculty of Medicine, University of Calgary, 3330 Hospital Dr. NW, Calgary, Alberta, Canada T2N 4N1. Phone: (403) 220-4569. Fax: (403) 270-7526. E-mail: yoon{at}ucalgary.ca.

Journal of Virology, October 1999, p. 8541-8548, Vol. 73, No. 10
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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