Oxidized low density lipoprotein-induced LFA-1-dependent adhesion and transendothelial migration of monocytes via the protein kinase C pathway.
Inflammatory and immune responses are highly relevant processes in the pathogenesis of atherosclerosis, as illustrated by the central event of monocyte accumulation in atherosclerotic plaques. Integrin LFA-1-mediated adhesion of circulating monocytes to the endothelium is a prerequisite for recruitment of monocytes to these areas. Integrin-mediated adhesion is tightly regulated and integrins are only functional in response to particular monocyte activation stimuli. We investigated the role of oxidized low-density lipoprotein (LDL) in adhesion of resting monocytes prepared by elutriation from endothelium. Our results showed that: (1) oxidized LDL (and MCP-1) induced both LFA-1-mediated adhesion of monocytes to endothelial cells and transendothelial migration of monocytes; (2) oxidized LDL functionally transformed monocyte LFA-1 to an activated form; (3) oxidized LDL induced F-actin polymerization and cytoskeletal rearrangement within seconds; and (4) the LDL-associated antioxidant, alpha-tocopherol, but not beta-tocopherol, inhibited both F-actin polymerization and LFA-1-mediated adhesion of monocytes, which paralleled the effect of protein kinase C (PKC) inhibitors. Our results indicate that oxidized LDL plays a pivotal role in triggering LFA-1 activation and LFA-1-mediated adhesion and transmigration of monocytes to sites of atherosclerotic plaques, via the PKC pathway.
Mine
Shinichiro
S
First Department of Internal Medicine, University of Occupational and Environmental Health, School of Medicine, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan.
Tabata
Takahiro
T
Wada
Youichiro
Y
Fujisaki
Takeshi
T
Iida
Takeshi
T
Noguchi
Noriko
N
Niki
Etsuo
E
Kodama
Tatsuhiko
T
Tanaka
Yoshiya
Y
D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000494:pharmacology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D004730:Endothelium, Vascular / Q000502:physiology*; D000939:Epitopes; D006801:Humans; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000502:physiology*; D009000:Monocytes / Q000502:physiology*; D010084:Oxidation-Reduction; D011493:Protein Kinase C / Q000502:physiology*; D024502:alpha-Tocopherol / Q000494:pharmacology
D018932:Chemokine CCL2; D000939:Epitopes; D008077:Lipoproteins, LDL; D016169:Lymphocyte Function-Associated Antigen-1; C099252:oxidized low density lipoprotein; D011493:Protein Kinase C; D024502:alpha-Tocopherol