Inhibition of mononuclear cell recruitment in aortic intima by treatment with anti-ICAM-1 and anti-LFA-1 monoclonal antibodies in hypercholesterolemic rats: implications of the ICAM-1 and LFA-1 pathway in atherogenesis.
To investigate the mechanism(s) for mononuclear cell recruitment in the arterial wall during the development of atherosclerosis, we studied intercellular adhesion molecule-1 (ICAM-1) and lymphocyte function-associated antigen-1 (LFA-1) expression in aortic intima from diet-induced hypercholesterolemic rats. ICAM-1 was barely found in the aortic walls from rats fed a normal chow diet; however, in rats on a cholesterol-rich diet for 4 weeks, ICAM-1 expression was markedly enhanced in the intimal endothelial cells of aortas. Enhanced expression of ICAM-1 on endothelial cells especially along the cellular borders in the abdominal aorta was almost invariably associated with increased adherence of mononuclear cells. Compared to control animals, in hypercholesterolemic rats, the numbers of intimal macrophages and T lymphocytes adhering to the "lesion-prone" areas of the abdominal aorta were significantly increased by 5.9-fold (p < 0.001) and 2.2-fold (p < 0.001), respectively. More than 85% of adherent macrophages exhibited LFA-1 antigen on the cellular membrane surface as assessed by immunostaining. To examine the participation of ICAM-1 and LFA-1 in adherence and migration of mononuclear cells, we administered monoclonal antibodies (mAb) against either ICAM-1 or LFA-1 into hypercholesterolemic rats after they were fed a cholesterol-rich diet for 2 weeks. Two weeks after the mAb treatment, the number of macrophages adhering to the intima was significantly inhibited by 42% (p < 0.001) with anti-ICAM-1 mAb and by 31% (p < 0.001) with anti-LFA-1 mAb compared to controls injected with mouse IgG. Combined injection with these two mAb increased the reduction of the number of macrophages in the intima to 58%. Furthermore, we found that the decrease in the number of macrophages that adhered to the intima was almost exclusively due to the reduction of LFA-1-positive macrophages. These results suggest that the ICAM-1 and LFA-1 pathway is involved in mononuclear-endothelial cell interaction during cholesterol-rich diet-induced atherogenesis.
Nie
Q
Q
Department of Pathology, University of Tsukuba, Japan.
Fan
J
J
Haraoka
S
S
Shimokama
T
T
Watanabe
T
T
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001012:Aorta, Abdominal / Q000276:immunology / Q000473:pathology; D001161:Arteriosclerosis / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D002464:Cell Migration Inhibition; D006937:Hypercholesterolemia / Q000150:complications / Q000276:immunology / Q000473:pathology*; D007150:Immunohistochemistry; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000276:immunology*; D007958:Leukocyte Count; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000473:pathology*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology*; D008297:Male; D051381:Rats; D013194:Staining and Labeling; D017539:Tunica Intima / Q000276:immunology / Q000473:pathology* / Q000648:ultrastructure
D000911:Antibodies, Monoclonal; D016169:Lymphocyte Function-Associated Antigen-1; D018799:Intercellular Adhesion Molecule-1