Role of Fas/FasL pathway in the activation of infiltrating cells in murine acute myocarditis caused by Coxsackievirus B3

Yoshinori Seko, Nobuhiko Kayagaki, Ken-ichiro Seino, Hideo Yagita, Ko Okumura, Ryozo Nagai
Journal of the American College of Cardiology 2002 April 17, 39 (8): 1399-403

OBJECTIVES: This study was designed to investigate the roles of Fas/FasL pathway in myocardial damage in murine acute myocarditis caused by Coxsackie virus B3 (CVB3).

BACKGROUND: Cardiac myocyte apoptosis rarely occurs in murine acute myocarditis caused by CVB3. Fas/FasL belong to the tumor necrosis factor receptor/ligand superfamily of costimulatory molecules and are known to play a critical role in the induction of apoptosis, as well as in the cytotoxicty mediated by T-cells and natural killer cells.

METHODS: We first analyzed the expression of Fas on cardiac myocytes in vivo and in vitro. Second, we examined the development of myocardial damage, in C3H/He mice treated with an anti-FasL monoclonal antibody (mAb), and in C3H/He-lpr/lpr mice and C3H/He-gld/gld mice infected with CVB3. Third, to investigate the effects of anti-FasL mAb treatment on the activation of the infiltrating cells, we examined the expression of interferon (IFN)-gamma and interleukin (IL)-2 as activation markers in the heart of mice by semiquantitative polymerase chain reaction.

RESULTS: Fas was markedly induced on cardiac myocytes with acute myocarditis. Myocardial inflammation was decreased in mice treated with anti-Fas L mAb, C3H/He-lpr/lpr mice and C3H/He-gld/gld mice. Anti-FasL mAb-treatment also decreased the expression of IFN-gamma, IL-2, inducible nitric oxide synthase and CVB3 genomes in myocardial tissue.

CONCLUSIONS: Our findings strongly suggested that the Fas/FasL pathway played a critical role in the development of massive myocardial necrosis through activation of infiltrating cells, and raise the possibility of immunotherapy by blocking the Fas/FasL pathway to prevent myocardial damage and improve the prognosis of patients with viral myocarditis.

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