Bea Florian, Puolakkainen Mirja H, McMillen Timothy, Hudson Francesca N, Mackman Nigel, Kuo Cho Chou, Campbell Lee Ann, Rosenfeld Michael E
Department of Pathobiology, University of Washington, Seattle, Wash 98195, USA.
Circ Res. 2003 Mar 7;92(4):394-401. doi: 10.1161/01.RES.0000059982.43865.75. Epub 2003 Feb 6.
Recent studies have suggested that infection with Chlamydia pneumoniae (C pneumoniae) may contribute to the instability of atherosclerotic plaques and thrombosis and is associated with acute coronary events. Tissue factor (TF), a potent prothrombotic molecule, is expressed by macrophages and other cell types within atherosclerotic lesions and plays an essential role in thrombus formation after plaque rupture. Therefore the effects of C pneumoniae on induction of TF expression in macrophages were investigated. Infection of RAW mouse macrophages with C pneumoniae induced a time-dependent increase in procoagulant activity, expression of TF protein, and TF mRNA. C pneumoniae infection stimulated increased binding of nuclear proteins to the consensus DNA sequence for Egr-1, a key response element within the TF promoter, and increased the expression of Egr-1 protein. Transient transfections of RAW cells with mutated TF promoter constructs showed that the Egr-1 binding region is an important transcriptional regulator of C pneumoniae-induced TF expression. Furthermore, C pneumoniae-stimulated phosphorylation of ERK1/2 and Elk-1 and pharmacological inhibition of mitogen-activated protein kinase activity reduced the expression of TF and Egr-1. Antibody and polymyxin B blocking of the Toll-like receptor 4 (TLR4) partially reduced the C pneumoniae-induced expression of TF and Egr-1. In conclusion, the C pneumoniae-induced increase in TF expression in macrophages is mediated in part by Egr-1, signaling through TLR4, and activation of the MEK-ERK1/2 pathway.
近期研究表明，肺炎衣原体（C pneumoniae）感染可能会导致动脉粥样硬化斑块不稳定和血栓形成，并与急性冠脉事件相关。组织因子（TF）是一种强效促血栓形成分子，由动脉粥样硬化病变内的巨噬细胞和其他细胞类型表达，在斑块破裂后的血栓形成中起关键作用。因此，研究了肺炎衣原体对巨噬细胞中TF表达诱导的影响。用肺炎衣原体感染RAW小鼠巨噬细胞会导致促凝血活性、TF蛋白表达和TF mRNA呈时间依赖性增加。肺炎衣原体感染刺激核蛋白与TF启动子内的关键反应元件Egr-1的共有DNA序列结合增加，并增加Egr-1蛋白的表达。用突变的TF启动子构建体对RAW细胞进行瞬时转染表明，Egr-1结合区域是肺炎衣原体诱导的TF表达的重要转录调节因子。此外，肺炎衣原体刺激的ERK1/2和Elk-1磷酸化以及丝裂原活化蛋白激酶活性的药理学抑制降低了TF和Egr-1的表达。用抗体和多粘菌素B阻断Toll样受体4（TLR4）可部分降低肺炎衣原体诱导的TF和Egr-1表达。总之，肺炎衣原体诱导的巨噬细胞中TF表达增加部分是由Egr-1介导的，通过TLR4信号传导以及MEK-ERK1/2途径的激活。
