Enhanced ERK-1/2 activation in mice susceptible to coxsackievirus-induced myocarditis
Mary Anne Opavsky, … , Janice Chan, Peter P. Liu
Mary Anne Opavsky, … , Janice Chan, Peter P. Liu
Published June 15, 2002
Citation Information: J Clin Invest. 2002;109(12):1561-1569. https://doi.org/10.1172/JCI13971.
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Article Immunology

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

Abstract

Group B coxsackieviral (CVB) infection commonly causes viral myocarditis. Mice are protected from CVB3 myocarditis by gene-targeted knockout of p56Lck(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.

Authors

Mary Anne Opavsky, Tami Martino, Marlene Rabinovitch, Josef Penninger, Chris Richardson, Martin Petric, Cathy Trinidad, Lisa Butcher, Janice Chan, Peter P. Liu

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ERK-1/2 activation in the heart is associated with susceptibility to CVB...
ERK-1/2 activation in the heart is associated with susceptibility to CVB3 myocarditis. (a) ERK-1/2 phosphorylation was increased in the hearts of CVB3-infected mice as early as day 1 postinfection (pi). By day 4, ERK-1/2 activation was more intense in myocarditis-susceptible A/J mice. Levels of phosphorylated ERK-1/2 (P-ERK-1/2) and total ERK-1/2 in the heart were determined by Western blot analysis of tissue homogenates from uninfected controls (0) and days 1, 2, and 4 after CVB3 infection. Results shown are representative of 5 mice per group. (b) The fold change in myocardial P-ERK-1/2:total ERK-1/2 ratios from day 0 (baseline set at 1) was determined following densitometry. By day 2 after infection, ERK-1/2 activation in the myocardium of A/J mice was elevated fivefold above the baseline in uninfected control mice. In A/J mice the intensity of ERK-1/2 phosphorylation continued to increase to eight times baseline by day 4 after infection. ERK-1/2 activation persisted at a lower level in the hearts of myocarditis-resistant C57BL/6 mice. Values are expressed as the mean fold change from baseline (± SEM; n = 5 per group). *P < 0.05 versus day 0 for A/J mice, and on day 4 A/J versus C57BL/6 mice; **P < 0.05 versus day 0 for C57BL/6 mice (ANOVA plus Bonferroni/Dunn post hoc testing).