title: CD137 (4-1BB) deficiency reduces atherosclerosis in hyperlipidemic mice.
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.
  
  
  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.
authors.affiliation: Division of Life and Pharmaceutical Science, Ewha Womans University, Seoul, Korea.
authors.forename: Hyung Jun
authors.initials: HJ
authors.lastname: Jeon
authors.forename: Jae-Hoon
authors.initials: JH
authors.lastname: Choi
authors.forename: In-Hyuk
authors.initials: IH
authors.lastname: Jung
authors.forename: Jong-Gil
authors.initials: JG
authors.lastname: Park
authors.forename: Mi-Ran
authors.initials: MR
authors.lastname: Lee
authors.forename: Mi-Ni
authors.initials: MN
authors.lastname: Lee
authors.forename: Bora
authors.initials: B
authors.lastname: Kim
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Yoo
authors.forename: Se-Jin
authors.initials: SJ
authors.lastname: Jeong
authors.forename: Dae-Yong
authors.initials: DY
authors.lastname: Kim
authors.forename: Jeong Euy
authors.initials: JE
authors.lastname: Park
authors.forename: Hyun-Young
authors.initials: HY
authors.lastname: Park
authors.forename: KyuBum
authors.initials: K
authors.lastname: Kwack
authors.forename: Beom Kyu
authors.initials: BK
authors.lastname: Choi
authors.forename: Byoung S
authors.initials: BS
authors.lastname: Kwon
authors.forename: Goo Taeg
authors.initials: GT
authors.lastname: Oh
mesh_terms: D053330:4-1BB Ligand / Q000502:physiology*; D000818:Animals; D020296:Animals, Congenic; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000209:etiology / Q000276:immunology / Q000517:prevention & control*; D003433:Crosses, Genetic; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004036:Diet, Atherogenic; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D025461:Feedback, Physiological; D005260:Female; D006937:Hypercholesterolemia / Q000150:complications* / Q000235:genetics; D018836:Inflammation Mediators / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology; D008213:Lymphocyte Activation; D008262:Macrophage Activation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D053330:4-1BB Ligand; D001057:Apolipoproteins E; D016207:Cytokines; D018836:Inflammation Mediators; D011973:Receptors, LDL; C505975:Tnfsf9 protein, mouse; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D007371:Interferon-gamma