Enhanced ERK-1/2 activation in mice susceptible to coxsackievirus-induced myocarditis.
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.
Opavsky
Mary Anne
MA
The Heart and Stroke/Richard Lewar Centre of Excellence, The University of Toronto, Toronto, Ontario, Canada. anne.opavsky@sickkids.ca
Martino
Tami
T
Rabinovitch
Marlene
M
Penninger
Josef
J
Richardson
Chris
C
Petric
Martin
M
Trinidad
Cathy
C
Butcher
Lisa
L
Chan
Janice
J
Liu
Peter P
PP
D000818:Animals; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D029822:Enterovirus B, Human / Q000254:growth & development / Q000502:physiology*; D004769:Enterovirus Infections / Q000201:enzymology* / Q000473:pathology / Q000821:virology; D004789:Enzyme Activation; D006801:Humans; D019169:Jurkat Cells; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009205:Myocarditis / Q000201:enzymology* / Q000473:pathology / Q000821:virology; D009206:Myocardium / Q000473:pathology; D019061:src-Family Kinases / Q000378:metabolism
D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D019061:src-Family Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases