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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 |
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Qing Nie, Jianglin
Fan, Seiji Haraoka, Tatsuro Shimokama, and Teruo Watanabe |
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Department
of Pathology, Institute of Basic Medical Sciences, University of Tsukuba,
Tsukuba, Japan |
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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-indued atherogenesis. |
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