Critical role for monocyte chemoattractant protein-1 and macrophage inflammatory
protein-1alpha in induction of experimental autoimmune myocarditis
and effective anti-monocyte chemoattractant
protein-1 gene therapy.
Goser
S, Ottl
R, Brodner
A, Dengler
TJ, Torzewski
J, Egashira
K, Rose NR, Katus
HA, Kaya
Z.
Department of Internal Medicine III,
BACKGROUND: Autoimmune myocarditis is a principal
cause of heart failure among young adults and is often a precursor of dilated cardiomyopathy. Monocyte chemoattractant protein-1 (MCP-1) and macrophage
inflammatory protein-1alpha (MIP-1alpha) are potent chemotactic
factors for mononuclear cells. The inflammatory infiltrate observed in
myocardial lesions of myocarditis consists of >70%
mononuclear cells. To determine their critical role in the pathogenesis of myocarditis, we inhibited mononuclear cell activation and
migration to see if it would affect disease severity and disease prevalence in
experimental autoimmune myocarditis (EAM). METHODS
AND RESULTS: In this report, we demonstrated that blockade of MCP-1 or
MIP-1alpha with monoclonal antibodies significantly reduced severity of myocarditis in BALB/c mice immunized with cardiac myosin.
Similar results were obtained when CCR2-/- and CCR5-/- mice were used. In
CCR2-/- mice, not only disease severity but also disease prevalence was
reduced. To further inhibit mononuclear cell activation and
migration, we transfected the mice before inducing
EAM with a dominant-negative inhibitor of MCP-1 gene (7ND). This transfection significantly reduced the disease severity, decreased mRNA expression levels, especially of
the chemokines RANTES, MIP-2, IP-10, MCP-1, T-cell
activation gene 3, and eotaxin in the myocardium, and
resulted in a reduction in cardiac myosin-induced interleukin-1 and
interleukin-4 and in an increase in interferon-gamma and interleukin-10
cytokine production by splenocytes. CONCLUSIONS:
Overall, these findings suggest that the chemokines
MCP-1 and MIP-1alpha, acting through their receptors CCR2 and CCR5, are
important in the induction of EAM and that inhibition of MCP-1 with 7ND gene transfection significantly reduced disease severity. This
strategy may be a new feasible form of gene therapy against autoimmune myocarditis.
PMID: 16316965 [PubMed - in process]