Role of Hck in the Pathogenesis of Encephalomyocarditis Virus-Induced Diabetes in Mice

ABSTRACTSoluble mediators such as interleukin-1ß, tumor necrosis factor alpha (TNF-a), and inducible nitric oxide synthase (iNOS) produced from activated macrophages play an important role in the destruction of pancreatic ß 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 ß cells, in mice infected with a low dose of EMC-D virus. We examined the activation of p59/p56Hck, p55Fgr, and p56/p53Lynin macrophages from DBA/2 mice infected with the virus. We found that p59/p56Hckshowed a marked increase in both autophosphorylation and kinase activity at 48 h after infection, whereas p55Fgrand p56/p53Lyndid not. The p59/p56Hckactivity 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/p56Hckactivity and almost complete inhibition of the production of TNF-a 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/p56Hck, plays an important role in the activation of macrophages and the subsequent production of TNF-a and nitric oxide, leading to the destruction of pancreatic ß cells, which results in the development of diabetes in mice infected with a low dose of EMC-D virus.