論文 - 詳細
| RRC ID | 47248 |
|---|---|
| 著者 | Matsumoto T, Sasaki N, Yamashita T, Emoto T, Kasahara K, Mizoguchi T, Hayashi T, Yodoi K, Kitano N, Saito T, Yamaguchi T, Hirata K. |
| タイトル | Overexpression of Cytotoxic T-Lymphocyte-Associated Antigen-4 Prevents Atherosclerosis in Mice. |
| ジャーナル | Arterioscler Thromb Vasc Biol |
| Abstract |
OBJECTIVE:Although T-cell-mediated chronic inflammation contributes to atherosclerosis development, the role of a negative regulatory molecule cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) in atherosclerosis is poorly understood. We investigated the effects of CTLA-4 overexpression on atherosclerosis in apolipoprotein E-deficient (Apoe(-/-)) mice. APPROACH AND RESULTS:We generated CTLA-4 transgenic (CTLA-4-Tg)/Apoe(-/-) mice that display constitutive cell surface and intracellular expression of CTLA-4 in T cells and assessed atherosclerosis at age 16 weeks. CTLA-4 overexpression significantly reduced atherosclerotic lesion formation and intraplaque accumulation of macrophage and CD4(+) T cells in the aortic root compared with controls. CTLA-4-Tg/Apoe(-/-) mice showed decreased numbers of effector CD4(+) T cells and decreased expression of costimulatory molecules CD80 and CD86, ligands for CTLA-4, and a costimulatory molecule CD28, on CD11c(+) dendritic cells compared with controls. Consistent with in vivo findings, in vitro experiments revealed that CD4(+) T cells from CTLA-4-Tg/Apoe(-/-) mice showed decreased proliferative capacity and proinflammatory cytokine production, downregulated CD80 expression on CD11c(+) dendritic cells, and suppressed the proliferation of other T cells by limiting the costimulatory pathway. Moreover, CD11c(+) dendritic cells from CTLA-4-Tg/Apoe(-/-) mice showed reduced proliferative activity of T cells in vitro, suggesting the suppression of dendritic cell maturation in vivo. CONCLUSIONS:CTLA-4 regulates atherosclerosis by suppressing proatherogenic immune responses and could be an attractive therapeutic target for atherosclerosis. |
| 巻・号 | 36(6) |
| ページ | 1141-51 |
| 公開日 | 2016-6-1 |
| DOI | 10.1161/ATVBAHA.115.306848 |
| PII | ATVBAHA.115.306848 |
| PMID | 27055906 |
| MeSH | Animals Aorta / immunology Aorta / metabolism* Aorta / pathology Aortic Diseases / genetics Aortic Diseases / immunology Aortic Diseases / metabolism Aortic Diseases / prevention & control* Apolipoproteins E / deficiency Apolipoproteins E / genetics Atherosclerosis / genetics Atherosclerosis / immunology Atherosclerosis / metabolism Atherosclerosis / prevention & control* B7-1 Antigen / metabolism B7-2 Antigen / metabolism CD11c Antigen / metabolism CD28 Antigens / metabolism CTLA-4 Antigen / genetics CTLA-4 Antigen / metabolism* Cell Proliferation Cells, Cultured Dendritic Cells / metabolism Female Genotype Lymphocyte Activation Macrophages / metabolism Male Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Phenotype Plaque, Atherosclerotic Signal Transduction T-Lymphocytes / immunology T-Lymphocytes / metabolism* Up-Regulation |
| IF | 6.604 |
| 引用数 | 29 |
| WOS 分野 | PERIPHERAL VASCULAR DISEASE HEMATOLOGY |
| リソース情報 | |
| 実験動物マウス | RBRC00144 |