MAPK/ERK通路
基因敲除
细胞生物学
促炎细胞因子
基因沉默
STAT1
转染
生物
巨噬细胞
磷酸化
信号转导
化学
免疫学
基因
炎症
体外
生物化学
作者
Na Li,James E. McLaren,Daryn Robert Michael,Mathew Clement,Ceri Alan Fielding,Dipak Purshottam Ramji
出处
期刊:Journal of Immunology
[The American Association of Immunologists]
日期:2010-09-01
卷期号:185 (5): 3041-3048
被引量:86
标识
DOI:10.4049/jimmunol.1000993
摘要
The proinflammatory cytokine IFN-gamma is a master regulator of atherosclerosis and mediates its cellular actions mainly through STAT1. Unfortunately, the impact of other IFN-gamma inducible pathways on STAT1 activation and the regulation of downstream responses associated with atherosclerosis in human macrophages are poorly understood and were therefore investigated. In this study, we demonstrate that the IFN-gamma-mediated phosphorylation of STAT1 on Ser(727), crucial for its maximal activity, was attenuated in human macrophages by pharmacological inhibition of ERK. In these cells, IFN-gamma induced changes in the expression of several key genes implicated in atherosclerosis, such as MCP-1, through an ERK-dependent mechanism. Additionally, the IFN-gamma-induced activity of STAT1-responsive promoters was attenuated by transfection of dominant-negative forms of ERK and other key components of this pathway. Furthermore, the IFN-gamma-induced uptake of acetylated and oxidized low-density lipoprotein by human macrophages was attenuated by pharmacological inhibition or RNA interference-mediated knockdown of ERK. These studies suggest a critical role for ERK signaling in the IFN-gamma-mediated changes in macrophage cholesterol homeostasis and gene expression during atherosclerosis.
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