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.
View: Text | PDF
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

×

Figure 3

Options: View larger image (or click on image) Download as PowerPoint
CVB3 replication in Jurkat cells is regulated by Src’s and the ERK-1/2 s...
CVB3 replication in Jurkat cells is regulated by Src’s and the ERK-1/2 signaling pathway. To assess infectivity, T cell lines (106) were treated with kinase inhibitors in DMSO or with DMSO alone (0) for 1 hour at 37°C, and then cells were infected with CVB3 (moi = 1) as described in Methods. Following incubation at 37°C for 48 hours, cells were frozen, then viral titers were determined by plaque assay. Treatment of (a) Jurkat and (b) JCaM cells with the MEK-1/2 inhibitor UO126 decreased CVB3 titers in Jurkat cells, but did not affect viral production in JCaM cells at the same doses of inhibitor. Treatment of (c) Jurkat and (d) JCaM cells with the MEK-1/2 inhibitor PD98059 significantly decreased CVB3 titers in Jurkat cells, but not in JCaM cells. Treatment of (e) Jurkat and (f) JCaM cells with the Src inhibitor PP2 decreased CVB3 titers in Jurkat cells, but not in JCaM cells. Titers were increased in JCaM cells treated with 0.5 μM PP2. Virus titers are expressed as mean pfu/106 cells (± SEM, n = 3 per group). *P < 0.05 DMSO versus kinase inhibitor for each cell type (ANOVA plus Bonferroni/Dunn post hoc testing).