Published online before print October 30, 2008, doi: 10.1161/CIRCRESAHA.108.178426
© 2008 American Heart Association, Inc.
Molecular Medicine |
Toll-Like Receptor 2 Mediates Apolipoprotein CIII–Induced Monocyte Activation
From the Department of Geriatrics and Vascular Medicine (A.K., K.S.) and the Life Science and Bioethics Research Center (A.K., M.O., M.Y.), Tokyo Medical and Dental University, Japan; Department of Cardiovascular Medicine (M.A., P.L., F.M.S.), Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass; WPI Immunology Frontier Research Center (S.U., S.A.), Osaka University, Japan; and Department of Nutrition (F.M.S.), Harvard School of Public Health, Boston, Mass.
Correspondence to Dr Akio Kawakami, Geriatrics and Vascular Medicine or Life Science and Bioethics Research Center, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 1138519, Japan. E-mail kawakami.vasc{at}tmd.ac.jp
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)-
B 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-B activation and β1 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-B 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.
Key Words: apolipoprotein • atherosclerosis • inflammation • monocyte • Toll-like receptor
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Circ. Res. 2008 103: 1348-1350.
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