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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CVB3 replication in neonatal mouse cardiac myocyte cultures is regulated...
CVB3 replication in neonatal mouse cardiac myocyte cultures is regulated by Src’s and the ERK-1/2 signaling pathway. (a) Cardiac myocytes, isolated from neonatal mice, were incubated with DMSO (0) or the MEK-1/2 inhibitor UO126 for 1 hour at 37°C, infected with CVB3 (moi = 5), and then incubated for 48 hours. (b) Cardiac myocytes were incubated with DMSO (0) or the Src’s PP2 for 1 hour at 37°C, then infected as above. Virus titers are expressed as mean pfu/2 × 105 cells (± SEM, n = 3 per group). *P < 0.05 DMSO versus kinase inhibitor for each cell type (ANOVA plus Bonferroni/Dunn post hoc testing). (c) ERK-1/2 activation following CVB3 infection in isolated cardiac myocytes was blocked by inhibition of ERK-1/2 and Src activation. The increase in ERK-1/2 phosphorylation observed 48 hours after viral infection was inhibited by treatment with 1 μM UO126 (UO) and 1 μM PP2. One result represents two experiments. Cell lysates were immunoblotted with anti–phospho-ERK-1/2 (P-ERK-1/2) and anti–total ERK-1/2 Ab’s. Fold change in P-ERK-1/2-total ERK-1/2 ratio is indicated.