title: Antibody binding to fas ligand attenuates inflammatory cell infiltration and cytokine secretion, leading to reduction of myocardial infarct areas and reperfusion injury.
abstract: 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.
authors.affiliation: Department of Cardiovascular Science and Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Shiraishi
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Toyozaki
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Tsukamoto
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Saito
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Masuda
authors.forename: Kenzo
authors.initials: K
authors.lastname: Hiroshima
authors.forename: Hidemi
authors.initials: H
authors.lastname: Ohwada
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Kobayashi
authors.forename: Michiaki
authors.initials: M
authors.lastname: Hiroe
mesh_terms: 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
chemical_list: D000906:Antibodies; D018932:Chemokine CCL2; D016207:Cytokines; D053222:Fas Ligand Protein; C505662:Faslg protein, rat; D008562:Membrane Glycoproteins; D012333:RNA, Messenger