Critical role for monocyte chemoattractant protein-1 and macrophage inflammatory protein-1α in induction of experimental autoimmune myocarditis and effective anti-monocyte chemoattractant protein-1 gene therapy

Stefan Göser, Renate Öttl, Alexander Brodner, Thomas J. Dengler, Jan Torzewski, Kensuke Egashira, Noel R. Rose, Hugo A. Katus, Ziya Kaya

研究成果: ジャーナルへの寄稿記事

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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-1α (MIP-1α) 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-1α 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-γ and interleukin-10 cytokine production by splenocytes. Conclusions - Overall, these findings suggest that the chemokines MCP-1 and MIP-1α, 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.

元の言語英語
ページ(範囲)3400-3407
ページ数8
ジャーナルCirculation
112
発行部数22
DOI
出版物ステータス出版済み - 11 1 2005

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All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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