期刊
CELL CYCLE
卷 14, 期 22, 页码 3580-3592出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/15384101.2015.1100771
关键词
atherosclerosis; macrophages; NFB; pro-inflammatory cytokines; repressor activator protein 1; signal transduction; telomeric protein
类别
资金
- General Program of National Natural Science Foundation of China [81270383]
Repressor activator protein 1 (Rap1) is essential for maintaining telomere length and structural integrity, but it also exerts other non-telomeric functions. The present study tested the hypothesis that Rap1 is released into the cytoplasm and induces production of pro-inflammatory cytokines via nuclear factor kappa B (NFB) signaling in macrophages, a cell type involved in the development and progression of atherosclerotic lesions. Western blotting analysis confirmed that Rap1 was present in the cytoplasm of differentiated human monocytic leukemia cells (THP-1, a macrophage-like cell line). Co-immunoprecipitation assay revealed a direct interaction between Rap1 and I kappa B kinase (IKK). Knockdown of Rap1 suppressed lipopolysaccharide-mediated activation of NFB, and phosphorylation of inhibitor of kappa B (IB) and p65 in THP-1 macrophages. The reduction of NFB activity was paralleled by a decreased production of NFB-dependent pro-inflammatory cytokines and an increased expression of IB (native NFB inhibitor) in various macrophage models with pro-inflammatory phenotype, including THP-1, mouse peritoneal macrophages and bone marrow-derived M1 macrophages. These changes were observed selectively in pro-inflammatory macrophages but not in bone marrow-derived M2 macrophages (with an anti-inflammatory phenotype), mouse lung endothelial cells, human umbilical vein endothelial cells or human aortic smooth muscle cells. Immunostaining revealed that Rap1 was localized mainly in macrophage-rich areas in human atherosclerotic plaques and that the presence of Rap1 was positively correlated with the advancement of the disease process. In pro-inflammatory macrophages, Rap1 promotes cytokine production via NFB activation favoring a pro-inflammatory environment which may contribute to the development and progression of atherosclerosis.
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