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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.

Hirasawa, K; Jun, HS; Han, HS; Zhang, ML; Hollenberg, MD; Yoon, JW
Journal of virology, 73(10):8541-8548, 1999
Journal Title
Journal of virology
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) p42(MAPK/ERK2)/p44(MAPK/ERK1), p38(MAPK), and p46/p54(JNK). 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.
MeSH terms
AnimalsCardiovirus Infections/metabolism*Cardiovirus Infections/prevention & controlCells, CulturedDiabetes Mellitus, Type 1/metabolismDiabetes Mellitus, Type 1/prevention & controlDiabetes Mellitus, Type 1/virology*Enzyme Inhibitors/pharmacologyEnzyme Inhibitors/therapeutic useMacrophage Activation/drug effectsMacrophages, Peritoneal/metabolismMacrophages, Peritoneal/virology*Maus Elberfeld virus*MiceMice, Inbred DBANitric Oxide/antagonists & inhibitorsNitric Oxide/metabolism*Protein-Tyrosine Kinases/antagonists & inhibitorsProtein-Tyrosine Kinases/metabolism*Signal Transduction*/drug effectsTyrphostins/pharmacologyTyrphostins/therapeutic use
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Journal Papers > School of Medicine / Graduate School of Medicine > Endocrinology & Metabolism
AJOU Authors
윤, 지원
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