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Role of Hck in the pathogenesis of encephalomyocarditis virus-induced diabetes in mice.

Choi, KS; Jun, HS; Kim, HN; Park, HJ; Eom, YW; Noh, HL; Kwon, H; Kim, HM; Yoon, JW
Journal of virology, 75(4):1949-1957, 2001
Journal Title
Journal of virology
Soluble mediators such as interleukin-1beta, tumor necrosis factor alpha (TNF-alpha), and inducible nitric oxide synthase (iNOS) produced from activated macrophages play an important role in the destruction of pancreatic beta cells in mice infected with a low dose of the D variant of encephalomyocarditis (EMC-D) virus. The tyrosine kinase signaling pathway was shown to be involved in EMC-D virus-induced activation of macrophages. This investigation was initiated to determine whether the Src family of kinases plays a role in the activation of macrophages, subsequently resulting in the destruction of beta cells, in mice infected with a low dose of EMC-D virus. We examined the activation of p59/p56(Hck), p55(Fgr), and p56/p53(Lyn) in macrophages from DBA/2 mice infected with the virus. We found that p59/p56(Hck) showed a marked increase in both autophosphorylation and kinase activity at 48 h after infection, whereas p55(Fgr) and p56/p53(Lyn) did not. The p59/p56(Hck) activity was closely correlated with the tyrosine phosphorylation level of Vav. Treatment of EMC-D virus-infected mice with the Src kinase inhibitor, PP2, resulted in the inhibition of p59/p56(Hck) activity and almost complete inhibition of the production of TNF-alpha and iNOS in macrophages and the subsequent prevention of diabetes in mice. On the basis of these observations, we conclude that the Src kinase, p59/p56(Hck), plays an important role in the activation of macrophages and the subsequent production of TNF-alpha and nitric oxide, leading to the destruction of pancreatic beta cells, which results in the development of diabetes in mice infected with a low dose of EMC-D virus.
MeSH terms
AnimalsBlotting, WesternCardiovirus Infections/immunologyCardiovirus Infections/pathologyCardiovirus Infections/virology*Diabetes Mellitus, Type 1/immunologyDiabetes Mellitus, Type 1/pathologyDiabetes Mellitus, Type 1/prevention & controlDiabetes Mellitus, Type 1/virology*Encephalomyocarditis virus/immunologyEncephalomyocarditis virus/pathogenicity*Enzyme ActivationIslets of Langerhans/pathologyMacrophage ActivationMacrophages/immunologyMacrophages/metabolismMacrophages/virology*MaleMiceMice, Inbred DBANitric Oxide Synthase/metabolismNitric Oxide Synthase Type IIProtein-Tyrosine Kinases/antagonists & inhibitorsProtein-Tyrosine Kinases/metabolism*Proto-Oncogene Proteins/antagonists & inhibitorsProto-Oncogene Proteins/metabolism*Proto-Oncogene Proteins c-hckTumor Necrosis Factor-alpha/metabolism
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Biochemistry & Molecular Biology
Journal Papers > School of Medicine / Graduate School of Medicine > Endocrinology & Metabolism
AJOU Authors
최, 경숙김, 현만
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