Published online before print February 6, 2003, doi: 10.1161/01.RES.0000059982.43865.75
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Submitted on August 12, 2002
Revised on January 23, 2003
Accepted on January 24, 2003
Chlamydia pneumoniae Induces Tissue Factor Expression in Mouse Macrophages via Activation of Egr-1 and the MEK-ERK1/2 Pathway
Florian Bea ;
From the Department of Pathobiology (F.B., M.H.P., C.C.K., L.A.C., M.E.R.), the Interdisciplinary Graduate Program in Nutritional Sciences (T.M., M.E.R.), the Department of Pathology (F.N.H., M.E.R.), University of Washington, Seattle Wash; and The Scripps Research Institute (N.M.), La Jolla, Calif.
* To whom correspondence should be addressed. E-mail: ssmjm{at}u.washington.edu.
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.
Key words: arteriosclerosis • Chlamydia pneumoniae • tissue factor • signal transduction
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