Enhanced ERK-1/2 activation in mice susceptible to coxsackievirus-induced myocarditis

• Published in: The Journal of clinical investigation 2002-06, Vol.109 (12), p.1561-1569
• Main Authors: Opavsky, Mary Anne, Martino, Tami, Rabinovitch, Marlene, Penninger, Josef, Richardson, Chris, Petric, Martin, Trinidad, Cathy, Butcher, Lisa, Chan, Janice, Liu, Peter P
• Format: Article
• Language: English
• Subjects: Animals; Disease Models, Animal; Disease Susceptibility; Enterovirus B, Human - growth & development; Enterovirus B, Human - physiology; Enterovirus Infections - enzymology; Enterovirus Infections - pathology; Enterovirus Infections - virology; Enzyme Activation; Humans; Jurkat Cells; Lymphocyte Specific Protein Tyrosine Kinase p56(lck) - genetics; Lymphocyte Specific Protein Tyrosine Kinase p56(lck) - metabolism; MAP Kinase Signaling System; Mice; Mice, Inbred A; Mice, Inbred C57BL; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases - metabolism; Myocarditis - enzymology; Myocarditis - pathology; Myocarditis - virology; Myocardium - pathology; src-Family Kinases - metabolism
• ISSN: 0021-9738
• DOI: 10.1172/jci0213971

Group B coxsackieviral (CVB) infection commonly causes viral myocarditis. Mice are protected from CVB3 myocarditis by gene-targeted knockout of p56(Lck)(Lck), the Src family kinase (Src) essential for T cell activation. Extracellular signal-regulated kinase 1 and 2 (ERK-1/2) can influence cell function downstream of Lck. Using T cell lines and neonatal cardiac myocytes we investigated the role of ERK-1/2 in CVB3 infection. In Jurkat T cells ERK-1/2 is rapidly activated by CVB3; but, this response is absent in Lck-negative JCaM T cells. Inhibition of ERK-1/2 with UO126 reduced CVB3 titers in Jurkat cells, but not in JCaM cells. In cardiac myocytes CVB3 activation of ERK-1/2 is blocked by the Src inhibitor PP2. In addition, viral production in myocytes is decreased by Src or ERK-1/2 inhibition. In vitro, in both immune and myocardial cells, ERK-1/2 is activated by CVB3 downstream of Lck and other Src's and is necessary for efficient CVB3 replication. In vivo, following CVB3 infection, ERK-1/2 activation is evident in the myocardium. ERK-1/2 activation is intense in the hearts of myocarditis-susceptible A/J mice. In contrast, significantly less ERK-1/2 activation is found in the hearts of myocarditis-resistant C57BL/6 mice. Therefore, the ERK-1/2 response to CVB3 infection may contribute to differential host susceptibility to viral myocarditis.