title: CD137-inducing factors from T cells and macrophages accelerate the destabilization of atherosclerotic plaques in hyperlipidemic mice.
abstract: 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.
authors: Department of Life Sciences, GT5 Program, and Department of Veterinary Pathology, College of Veterinary Medicine, Seoul National University, Seoul, Korea;
authors: In-Hyuk
authors: IH
authors: Jung
authors: Department of Life Science, College of Natural Sciences, Hanyang University, Seoul, Korea;
authors: Jae-Hoon
authors: JH
authors: Choi
authors: Department of Life Sciences, GT5 Program, and.
authors: Jing
authors: J
authors: Jin
authors: Department of Life Sciences, GT5 Program, and.
authors: Se-Jin
authors: SJ
authors: Jeong
authors: Department of Life Sciences, GT5 Program, and.
authors: Sejin
authors: S
authors: Jeon
authors: Department of Life Sciences, GT5 Program, and.
authors: Chaeji
authors: C
authors: Lim
authors: Department of Life Sciences, GT5 Program, and.
authors: Mi-Ran
authors: MR
authors: Lee
authors: Department of Life Sciences, GT5 Program, and.
authors: Ji-Young
authors: JY
authors: Yoo
authors: Department of Life Sciences, GT5 Program, and.
authors: Seong-Keun
authors: SK
authors: Sonn
authors: Immune Cell Production Unit, Program for Immunotherapeutic Research, and.
authors: Young Ho
authors: YH
authors: Kim
authors: Cancer Immunology Branch, Division of Cancer Biology, National Cancer Center, Goyang, Korea; and.
authors: Beom Kyu
authors: BK
authors: Choi
authors: Cancer Immunology Branch, Division of Cancer Biology, National Cancer Center, Goyang, Korea; and.
authors: Byoung S
authors: BS
authors: Kwon
authors: Department of Microbiology, Graduate School of Medicine, Ewha Womans University, Seoul, Korea;
authors: Ju-Young
authors: JY
authors: Seoh
authors: Department of Medicine, Asan Medical Center, University of Ulsan, Seoul, Korea.
authors: Cheol Whan
authors: CW
authors: Lee
authors: Department of Veterinary Pathology, College of Veterinary Medicine, Seoul National University, Seoul, Korea; gootaeg@ewha.ac.kr daeyong@snu.ac.kr.
authors: Dae-Yong
authors: DY
authors: Kim
authors: Department of Life Sciences, GT5 Program, and gootaeg@ewha.ac.kr daeyong@snu.ac.kr.
authors: Goo Taeg
authors: GT
authors: Oh
mesh_terms: D053330:4-1BB Ligand / Q000276:immunology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D050197:Atherosclerosis / Q000276:immunology / Q000378:metabolism*; D006949:Hyperlipidemias / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D058226:Plaque, Atherosclerotic / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*
chemical_list: D053330:4-1BB Ligand; C505975:Tnfsf9 protein, mouse; D007371:Interferon-gamma
keywords: ApoE-knockout mice; MMP; advanced atheroma