Published online before print April 10, 2008

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Copyright © 2008 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2008.070207

Accepted for publication February 5, 2008.

Article

Interleukin-13 Protects Against Experimental Autoimmune Myocarditis by Regulating Macrophage Differentiation

Daniela Cihakova^*@, Jobert G. Barin^*, Marina Afanasyeva, Miho Kimura^*, DeLisa Fairweather^*, Michael Berg^¶, Monica V. Talor^*, G. Christian Baldeviano^¶, Sylvia Frisancho, Kathleen Gabrielson^||, Djahida Bedja^||, and Noel R. Rose^*¶

From the Departments of Pathology,* and Molecular and Comparative Pathobiology,^|| and the Graduate Program in Immunology, The Johns Hopkins University School of Medicine, Baltimore, Maryland; the W. Harry Feinstone Department of Molecular Microbiology and Immunology,^¶ and the Department of Environmental Health Sciences, the Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland; and the Cardiovascular Research Group, Faculty of Medicine, University of Calgary, Calgary, Canada

^@ To whom correspondence should be addressed. E-mail: dcihako1{at}jhmi.edu.

	Abstract

We report here that interleukin (IL)-13 protects BALB/c mice from myocarditis, whether induced by peptide immunization or by viral infection. In contrast to mild disease in IL-4 knockout (KO) BALB/c mice, IL-13 KO BALB/c mice developed severe coxsackievirus B3 (CVB3)-induced autoimmune myocarditis and myocarditogenic peptide-induced experimental autoimmune myocarditis. Such severe disease was characterized by increased cardiac inflammation, increased total intracardiac CD45⁺ leukocytes, elevated anti-cardiac myosin autoantibodies, and increased cardiac fibrosis. Echocardiography revealed that IL-13 KO mice developed severe dilated cardiomyopathy with impaired cardiac function and heart failure. Hearts of IL-13 KO mice had increased levels of the proinflammatory and profibrotic cytokines IL-1, IL-18, interferon-, transforming growth factor-1, and IL-4 as well as histamine. The hallmark of the disease in IL-13 KO mice was the up-regulation of T-cell responses. CD4⁺ T cells were increased in IL-13 KO hearts both proportionally and in absolute number. Splenic T cells from IL-13 KO mice were highly activated, and myosin stimulation additionally increased T-cell proliferation. CD4⁺CD25⁺Foxp3⁺ regulatory T-cell numbers were decreased in the spleens of IL-13 KO mice. IL-13 deficiency led to decreased levels of alternatively activated CD206⁺ and CD204⁺ macrophages and increased levels of classically activated macrophages. IL-13 KO mice had increased caspase-1 activation, leading to increased production of both IL-1 and IL-18. Therefore, IL-13 protects against myocarditis by modulating monocyte/macrophage populations and by regulating their function.