RRC ID 6004
Author Jeon HJ, Choi JH, Jung IH, Park JG, Lee MR, Lee MN, Kim B, Yoo JY, Jeong SJ, Kim DY, Park JE, Park HY, Kwack K, Choi BK, Kwon BS, Oh GT.
Title CD137 (4-1BB) deficiency reduces atherosclerosis in hyperlipidemic mice.
Journal Circulation
Abstract BACKGROUND:The tumor necrosis factor receptor superfamily, which includes CD40, LIGHT, and OX40, plays important roles in atherosclerosis. CD137 (4-1BB), a member of the tumor necrosis factor receptor superfamily, has been reported to be expressed in human atherosclerotic lesions. However, limited information is available on the precise role of CD137 in atherosclerosis and the effects of blocking CD137/CD137 ligand signaling on lesion formation.
METHODS AND RESULTS:We generated CD137-deficient apolipoprotein E-knockout mice (ApoE(-/-) CD137(-/-)) and LDL-receptor-knockout mice (Ldlr(-/-)CD137(-/-)) to investigate the role of CD137 in atherogenesis. The deficiency of CD137 induced a reduction in atherosclerotic plaque lesions in both atherosclerosis mouse models, which was attributed to the downregulation of cytokines such as interferon-gamma, monocyte chemoattractant protein-1, and tumor necrosis factor-alpha. CD137 signaling promoted the production of inflammatory molecules, including monocyte chemoattractant protein-1, interleukin-6, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1, in endothelial cells. Stimulation of CD137 ligand signaling activated monocytes/macrophages and augmented the production of proinflammatory cytokines in atherosclerotic vessels.
CONCLUSIONS:CD137/CD137 ligand signaling plays multiple roles in the progression of atherosclerosis, and thus, blockade of this pathway is a promising therapeutic target for the disease.
Volume 121(9)
Pages 1124-33
Published 2010-3-9
DOI 10.1161/CIRCULATIONAHA.109.882704
PMID 20176988
MeSH 4-1BB Ligand / physiology* Animals Animals, Congenic Apolipoproteins E / deficiency Apolipoproteins E / genetics Atherosclerosis / etiology Atherosclerosis / immunology Atherosclerosis / prevention & control* Crosses, Genetic Cytokines / biosynthesis Cytokines / genetics Diet, Atherogenic Disease Models, Animal Endothelium, Vascular / metabolism Endothelium, Vascular / pathology Feedback, Physiological Female Hypercholesterolemia / complications* Hypercholesterolemia / genetics Inflammation Mediators / metabolism Interferon-gamma / immunology Lymphocyte Activation Macrophage Activation Male Mice Mice, Inbred C57BL Mice, Knockout Receptors, LDL / deficiency Receptors, LDL / genetics Signal Transduction T-Lymphocytes / immunology Tumor Necrosis Factor Receptor Superfamily, Member 9 / deficiency Tumor Necrosis Factor Receptor Superfamily, Member 9 / genetics Tumor Necrosis Factor Receptor Superfamily, Member 9 / physiology*
IF 23.603
Times Cited 85
Mice RBRC00267