title: Role of Hck in the pathogenesis of encephalomyocarditis virus-induced diabetes in mice.
abstract: 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.
authors.affiliation: Laboratory of Endocrinology, Institute for Medical Sciences, Ajou University School of Medicine, Suwon, Korea.
authors.forename: K S
authors.initials: KS
authors.lastname: Choi
authors.forename: H S
authors.initials: HS
authors.lastname: Jun
authors.forename: H N
authors.initials: HN
authors.lastname: Kim
authors.forename: H J
authors.initials: HJ
authors.lastname: Park
authors.forename: Y W
authors.initials: YW
authors.lastname: Eom
authors.forename: H L
authors.initials: HL
authors.lastname: Noh
authors.forename: H
authors.initials: H
authors.lastname: Kwon
authors.forename: H M
authors.initials: HM
authors.lastname: Kim
authors.forename: J W
authors.initials: JW
authors.lastname: Yoon
mesh_terms: D000818:Animals; D015153:Blotting, Western; D018188:Cardiovirus Infections / Q000276:immunology / Q000473:pathology / Q000821:virology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000473:pathology / Q000517:prevention & control / Q000821:virology*; D004686:Encephalomyocarditis virus / Q000276:immunology / Q000472:pathogenicity*; D004789:Enzyme Activation; D007515:Islets of Langerhans / Q000473:pathology; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000821:virology*; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051572:Proto-Oncogene Proteins c-hck; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D011518:Proto-Oncogene Proteins; D014409:Tumor Necrosis Factor-alpha; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D011505:Protein-Tyrosine Kinases; C496632:Hck protein, mouse; D051572:Proto-Oncogene Proteins c-hck