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FASEB J. 2014 Nov;28(11):4779-91. doi: 10.1096/fj.14-253732. Epub 2014 Jul 24.

CD137-inducing factors from T cells and macrophages accelerate the destabilization of atherosclerotic plaques in hyperlipidemic mice.

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Department of Life Sciences, GT5 Program, and Department of Veterinary Pathology, College of Veterinary Medicine, Seoul National University, Seoul, Korea;
Department of Life Science, College of Natural Sciences, Hanyang University, Seoul, Korea;
Department of Life Sciences, GT5 Program, and.
Immune Cell Production Unit, Program for Immunotherapeutic Research, and.
Cancer Immunology Branch, Division of Cancer Biology, National Cancer Center, Goyang, Korea; and.
Department of Microbiology, Graduate School of Medicine, Ewha Womans University, Seoul, Korea;
Department of Medicine, Asan Medical Center, University of Ulsan, Seoul, Korea.
Department of Veterinary Pathology, College of Veterinary Medicine, Seoul National University, Seoul, Korea;
Department of Life Sciences, GT5 Program, and


CD137 (4-1BB), a member of the tumor necrosis factor receptor superfamily, has been reported to be expressed in atherosclerotic plaques, and to promote lesion formation. However, the role of CD137 in mediating atherosclerotic plaque stability and the possible underlying molecular and cellular mechanisms are poorly understood. Here, apolipoprotein E-deficient (ApoE(-/-)) and CD137-deficient ApoE(-/-) (ApoE(-/-)CD137(-/-)) mice fed a chow diet for 66 wk were used. CD137 induces plaque instability, which is characterized by increased plaque necrosis, decreased collagen content, decreased vascular smooth muscle cell (VSMC) content, and increased macrophage infiltration. CD137 also increases the infiltration of effector T (Teff) cells into plaque lesion sites, resulting in increased interferon-γ (IFN-γ) expression. Interestingly, Teff-cell-derived IFN-γ inhibits collagen synthesis in atherosclerotic plaques. Furthermore, CD137 activation increases the apoptosis of VSMCs, possibly by decreasing the antiapoptotic regulator, Bcl-2, and subsequently up-regulating cleaved caspase-3. In macrophages, activation of CD137 signaling boosted the oxidized low density lipoprotein-induced expression of matrix metalloproteinase 9 via the p38 mitogen-activated protein kinase and extracellular signal-regulated kinase1/2 signaling pathways. In summary, activation of CD137 signaling decreases the stability of advanced atherosclerotic plaques via its combined effects on Teff cells, VSMCs, and macrophages.


ApoE-knockout mice; MMP; advanced atheroma

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