Immune response is critically involved in determining the course of viral
myocarditis and
immunomodulation. Different
cytokines may have either deleterious or protective effects. Following acute Coxsackievirus B3
infection, intramyocardial
inflammation is associated with altered myocardial
matrix metalloproteinase (
MMP) expression and
left ventricular dysfunction. In this study, we evaluated the effect of exogenous
interleukin-4 treatment on myocardial
inflammation,
MMPs and left ventricular function in Coxsackievirus B3-induced acute murine
myocarditis. Eight-week-old inbred male BALB/c (H-2d) mice (The Jackson Laboratory, Bar Harbor, Maine, USA) were used. Myocardial
inflammation was measured by immunohistochemical detection of CD3(+)-, CD8a(+)-T-lymphocytes, and CD11b+ macrophages. In situ hybridization was used to detect enteroviral genome in the myocardium. Semi-quantitative
reverse transcriptase polymerase chain reaction (RT-PCR) was employed to detect
cytokine and
MMP mRNA.
MMP activity was quantified by zymography analysis. Detection of myocytolysis was performed by
Luxol fast blue staining. In the early acute phase, in comparison to infected mice without treatment,
interleukin-4 administration (200 ng daily) reduced intramyocardial
inflammation (CD3+ lymphocytes: 55.3+/-7.0 vs. 72.1+/-13.7 cells/mm2, P < 0.05; CD8a+ lymphocytes: 31.7+/-3.6 vs. 64.2+/-7.7 cells/mm2, P < 0.05; CD11b+ macrophages: 5.1+/-2.3 vs. 13.2+/-2.5 cells/mm2, P < 0.05). It also down-regulated
interleukin-2 (IL) (1.7-fold, P < 0.001) but increased
transforming growth factor-beta1 (TGF) (1.5-fold, P < 0.001) and
IL-4 (1.4-fold, P < 0.001).
IL-4 suppressed
MMP-2/-3/-9 transcription and activity. These biochemical alterations were accompanied by a significant improvement of left ventricular function as assessed by Milar tip
catheter (left ventricular endsystolic pressure, 1.3-fold, P < 0.01; dP/dt max, 1.5-fold, P < 0.01).
Immunomodulation by exogenous
IL-4 treatment may lead to an anti-inflammatory effect with the inhibition of Th1 cell phenotypic response, which may further mediate the down-regulation of
MMPs. A significant suppression of
MMPs may mainly contribute to an improvement of
left ventricular dysfunction in acute murine CVB3-induced
myocarditis.