CD137 (4-1BB) deficiency reduces atherosclerosis in hyperlipidemic mice

Hyung Jun Jeon, Jae Hoon Choi, In Hyuk Jung, Jong Gil Park, Mi Ran Lee, Mi Ni Lee, Bora Kim, Ji Young Yoo, Se Jin Jeong, Dae Yong Kim, Jeong Euy Park, Hyun Young Park, Kyubum Kwack, Beom Kyu Choi, Byoung S. Kwon, Goo Taeg Oh

Research output: Contribution to journalArticlepeer-review

100 Scopus citations

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 (ApoECD137) and LDL-receptor-knockout mice (LdlrCD137) 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-γ, monocyte chemoattractant protein-1, and tumor necrosis factor-α. 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.

Original languageEnglish
Pages (from-to)1124-1133
Number of pages10
JournalCirculation
Volume121
Issue number9
DOIs
StatePublished - Mar 2010

Keywords

  • Atherosclerosis
  • CD137
  • CD137 ligand
  • Immune system

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