title: Toll-like receptor 2 mediates apolipoprotein CIII-induced monocyte activation.
abstract: Apolipoprotein (apo)CIII predicts risk for coronary heart disease. We recently reported that apoCIII directly activates human monocytes. Recent evidence indicates that toll-like receptor (TLR)2 can contribute to atherogenesis through transduction of inflammatory signals. Here, we tested the hypothesis that apoCIII activates human monocytoid THP-1 cells through TLR2. ApoCIII induced the association of TLR2 with myeloid differentiation factor 88, activated nuclear factor (NF)-kappaB in THP-1 cells, and increased their adhesion to human umbilical vein endothelial cells (HUVECs). Anti-TLR2 blocking antibody, but not anti-TLR4 blocking antibody or isotype-matched IgG, inhibited these processes (P<0.05). ApoCIII bound with high affinity to human recombinant TLR2 protein and showed a significantly higher (P<0.05) and saturable binding to 293 cells overexpressing human TLR2 than to parental 293 cells with no endogenous TLR2. Overexpression of TLR2 in 293 cells augmented apoCIII-induced NF-kappaB activation and beta(1) integrin expression, processes inhibited by anti-apoCIII antibody as well as anti-TLR2 antibody. Exposure of peripheral blood monocytes isolated from C57BL/6 (wild-type) mice to apoCIII activated their NF-kappaB and increased their adhesiveness to HUVECs. In contrast, apoCIII did not activate monocytes from TLR2-deficient mice. Finally, intravenous administration to C57BL/6 mice of apoCIII-rich very-low-density lipoprotein (VLDL), but not of apoCIII-deficient VLDL, activated monocytes and increased their adhesiveness to HUVECs, processes attenuated by anti-TLR2 or anti-apoCIII antibody. ApoCIII-rich VLDL did not activate monocytes from TLR2-deficient mice. In conclusion, apoCIII activated monocytes at least partly through a TLR2-dependent pathway. The present study identifies a novel mechanism for proinflammatory and proatherogenic effects of apoCIII and a role for TLR2 in atherosclerosis induced by atherogenic lipoproteins.
authors.affiliation: Department of Geriatrics and Vascular Medicine, Tokyo Medical and Dental University, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Kawakami
authors.forename: Mizuko
authors.initials: M
authors.lastname: Osaka
authors.forename: Masanori
authors.initials: M
authors.lastname: Aikawa
authors.forename: Satoshi
authors.initials: S
authors.lastname: Uematsu
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Peter
authors.initials: P
authors.lastname: Libby
authors.forename: Kentaro
authors.initials: K
authors.lastname: Shimokado
authors.forename: Frank M
authors.initials: FM
authors.lastname: Sacks
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yoshida
mesh_terms: D000818:Animals; D053305:Apolipoprotein C-III / Q000378:metabolism / Q000502:physiology*; D001055:Apolipoproteins B / Q000378:metabolism; D050197:Atherosclerosis / Q000209:etiology / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D051195:Toll-Like Receptor 2 / Q000378:metabolism / Q000502:physiology*
chemical_list: D053305:Apolipoprotein C-III; D001055:Apolipoproteins B; D008024:Ligands; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2