Immunomodulation by interleukin-4 suppresses matrix metalloproteinases and improves cardiac function in murine myocarditis.
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.
Li
Jun
J
Department of Internal Medicine II, Charité-Campus Benjamin Franklin, Hindenburgdamm 30, D-12200 Berlin, Germany.
Leschka
Sebastian
S
Rutschow
Susanne
S
Schwimmbeck
Peter Lothar
PL
Husmann
Lars
L
Noutsias
Michel
M
Westermann
Dirk
D
Poller
Wolfgang
W
Zeichhardt
Heinz
H
Klingel
Karin
K
Tschope
Carsten
C
Schultheiss
Heinz-Peter
HP
Pauschinger
Matthias
M
D000818:Animals; D003384:Coxsackievirus Infections / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D029822:Enterovirus B, Human; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics; D015847:Interleukin-4 / Q000627:therapeutic use*; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008807:Mice, Inbred BALB C; D009205:Myocarditis / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D009206:Myocardium / Q000201:enzymology; D012333:RNA, Messenger / Q000032:analysis; D016277:Ventricular Function, Left / Q000187:drug effects*; D019562:Viral Load
D007376:Interleukin-2; D061965:Matrix Metalloproteinase Inhibitors; D012333:RNA, Messenger; D015847:Interleukin-4; D007371:Interferon-gamma; D019278:Matrix Metalloproteinase 3; D020780:Matrix Metalloproteinase 9