Antibody binding to fas ligand attenuates inflammatory cell infiltration and cytokine secretion, leading to reduction of myocardial infarct areas and reperfusion injury.
Fas ligand (FasL) induces apoptotic cell death when bound to Fas antigen. The engagement of FasL has anti-inflammatory effects through the prevention of cell proliferation and cytokine secretion. However, the role of FasL in myocardial ischemia/reperfusion (MI/R) injury is unclear. We examined the expression of FasL mRNA in the myocardium of MI/R rats by ligating the left coronary artery for 30 minutes and allowing reperfusion to occur for 0, 1, 3, and 24 hours. The expression of FasL mRNA was enhanced 1 hour after reperfusion, and enhanced levels were consistently seen after 24 hours of reperfusion. FasL immunostaining was observed on neutrophils, macrophages, T cells, and vascular endothelial cells. We then assessed the potential role of FasL in the cell proliferation and cytokine production seen in MI/R injury after 24 hours of reperfusion. Rats were divided into three groups; Group A, without treatment; Group B, treated with nonspecific rabbit IgG; and Group C, treated with anti-FasL antibody. Anti-FasL antibody or rabbit IgG were administered intravenously before coronary artery occlusion. In Group C, interleukin-1beta and interleukin-2 mRNA levels were decreased, and neutrophil and T cell accumulation was attenuated. The infarct area determined by triphenyltetrazolium chloride staining was significantly smaller in Group C (18 +/- 4%) than in Group A (34 +/- 2%) or Group B (33 +/- 4%) (p< 0.0001). However, there was no significant difference in the prevalence of terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end-labeling-positive cardiomyocytes among the three groups. These findings suggest that the cardioprotective effect of anti-FasL antibody is due to its anti-inflammatory action, rather than antiapoptotic action. The Fas/FasL system may be involved in the development of MI/R injury.
Shiraishi
Hirokazu
H
Department of Cardiovascular Science and Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.
Toyozaki
Tetsuya
T
Tsukamoto
Yoshiaki
Y
Saito
Toshihiro
T
Masuda
Yoshiaki
Y
Hiroshima
Kenzo
K
Ohwada
Hidemi
H
Kobayashi
Nobuyuki
N
Hiroe
Michiaki
M
D000818:Animals; D000906:Antibodies / Q000627:therapeutic use*; D017209:Apoptosis; D018932:Chemokine CCL2 / Q000502:physiology; D016207:Cytokines / Q000096:biosynthesis*; D053222:Fas Ligand Protein; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D009203:Myocardial Infarction / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009504:Neutrophils / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley
D000906:Antibodies; D018932:Chemokine CCL2; D016207:Cytokines; D053222:Fas Ligand Protein; C505662:Faslg protein, rat; D008562:Membrane Glycoproteins; D012333:RNA, Messenger