EXPERIMENTAL STUDY
Role of Fas/FasL pathway in the activation of infiltrating cells in murine acute myocarditis caused by Coxsackievirus B3
Yoshinori Seko, MD*  ,*,
Nobuhiko Kayagaki, PhD,
Ken-ichiro Seino, MD,
Hideo Yagita, PhD,
Ko Okumura, PhD and
Ryozo Nagai, MD*
* Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
Department of Immunology, School of Medicine, Juntendo University, Tokyo, Japan
Institute for Adult Diseases, Asahi Life Foundation, Tokyo, Japan
Manuscript received August 17, 2001;
revised manuscript received January 14, 2002,
accepted January 22, 2002.
* Reprint requests and correspondence: Dr. Yoshinori Seko, Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
sekoyosh-tky{at}umin.ac.jp
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 myoctyes 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.
|
Abbreviations and Acronyms
| | CTL | | cytotoxic T lymphocyte | | CVB3 | | Coxsackie virus B3 | | DNA | | deoxyribonucleic acid | | GAPDH | | glyceraldehyde-3-phospate dehydrogenase | | IFN | | interferon | | IgG | | immunoglobulin G | | IL | | interleukin | | iNOS | | inducible nitric oxide synthase | | mAb | | monoclonal antibody | | NK cell | | natural killer cell | | PCR | | polymerase chain reaction | | RNA | | ribonucleic acid | | Th | | T helper cell | | TSA | | tyramide signal amplification |
|
This article has been cited by other articles:
|
|
|
|
 
A. Niessner, P. J. Hohensinner, K. Rychli, S. Neuhold, G. Zorn, B. Richter, M. Hulsmann, R. Berger, D. Mortl, K. Huber, et al.
Prognostic value of apoptosis markers in advanced heart failure patients
Eur. Heart J.,
April 1, 2009;
30(7):
789 - 796.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. M. de Oliveira, R. L. Diniz, W. Batista, M. M. Batista, C. Bani Correa, T. C. de Araujo-Jorge, and A. Henriques-Pons
Fas Ligand-Dependent Inflammatory Regulation in Acute Myocarditis Induced by Trypanosoma cruzi Infection
Am. J. Pathol.,
July 1, 2007;
171(1):
79 - 86.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Seko, H. Yagita, K. Okumura, M. Azuma, and R. Nagai
Roles of programmed death-1 (PD-1)/PD-1 ligands pathway in the development of murine acute myocarditis caused by coxsackievirus B3
Cardiovasc Res,
July 1, 2007;
75(1):
158 - 167.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Zaragoza, M. Saura, E. Y. Padalko, E. Lopez-Rivera, T. R. Lizarbe, S. Lamas, and C. J. Lowenstein
Viral protease cleavage of inhibitor of {kappa}B{alpha} triggers host cell apoptosis
PNAS,
December 12, 2006;
103(50):
19051 - 19056.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Niu, A. Azfer, and P. E. Kolattukudy
Monocyte-specific Bcl-2 expression attenuates inflammation and heart failure in monocyte chemoattractant protein-1 (MCP-1)-induced cardiomyopathy
Cardiovasc Res,
July 1, 2006;
71(1):
139 - 148.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. L. Mann
Determinants of Myocardial Recovery in Myocarditis: Has the Time Come for Molecular Fingerprinting?
J. Am. Coll. Cardiol.,
September 20, 2005;
46(6):
1043 - 1044.
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Goren, J. Cuenca, P. Martin-Sanz, and L. Bosca
Attenuation of NF-{kappa}B signalling in rat cardiomyocytes at birth restricts the induction of inflammatory genes
Cardiovasc Res,
November 1, 2004;
64(2):
289 - 297.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Yndestad, A. M Holm, F. Muller, S. Simonsen, S. S Froland, L. Gullestad, and P. Aukrust
Enhanced expression of inflammatory cytokines and activation markers in T-cells from patients with chronic heart failure
Cardiovasc Res,
October 15, 2003;
60(1):
141 - 146.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Twu, N. Q. Liu, W. Popik, M. Bukrinsky, J. Sayre, J. Roberts, S. Rania, V. Bramhandam, K. P. Roos, W. R. MacLellan, et al.
Cardiomyocytes undergo apoptosis in human immunodeficiency virus cardiomyopathy through mitochondrion- and death receptor-controlled pathways
PNAS,
October 29, 2002;
99(22):
14386 - 14391.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
