Role of Fas/FasL pathway in the activation of infiltrating cells in murine acute myocarditis caused by Coxsackievirus B3.
OBJECTIVE
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.
Seko
Yoshinori
Y
Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan. sekoyosh-tky@umin.ac.jp
Kayagaki
Nobuhiko
N
Seino
Ken-ichiro
K
Yagita
Hideo
H
Okumura
Ko
K
Nagai
Ryozo
R
D000208:Acute Disease; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D016207:Cytokines / Q000187:drug effects / Q000276:immunology; D004730:Endothelium, Vascular / Q000737:chemistry; D029822:Enterovirus B, Human / Q000276:immunology*; D004769:Enterovirus Infections / Q000150:complications* / Q000453:epidemiology / Q000209:etiology*; D053222:Fas Ligand Protein; D005260:Female; D007073:Immunoglobulin E / Q000494:pharmacology; D015994:Incidence; D007371:Interferon-gamma / Q000494:pharmacology; D008297:Male; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D009205:Myocarditis / Q000150:complications* / Q000453:epidemiology / Q000209:etiology*; D011247:Pregnancy; D019014:fas Receptor / Q000502:physiology*
D000911:Antibodies, Monoclonal; D016207:Cytokines; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D019014:fas Receptor; D007073:Immunoglobulin E; D007371:Interferon-gamma