Published online before print September 2, 2004, doi: 10.1161/01.RES.0000143900.19798.47
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Submitted on June 25, 2004
Revised on July 23, 2004
Accepted on August 19, 2004
Flow-Dependent Regulation of Endothelial Toll-Like Receptor 2 Expression Through Inhibition of SP1 Activity
Stefan Dunzendorfer ;
From the Scripps Research Institute, Department of Immunology, La Jolla, Calif.
* To whom correspondence should be addressed. E-mail: tobias{at}scripps.edu.
Innate immune system activation is associated with atherosclerotic lesion development. The specific sites of lesion development are believed to be defined by the shear stress of blood flow. Consequently, we investigated the responsiveness of human coronary artery endothelial cells (HCAECs) to toll-like receptor (TLR) 2 and 4 agonists in an in vitro model of chronic laminar flow. HCAECs under chronic laminar flow were found to be normally responsive to lipopolysaccharide (and tumor necrosis factor) in terms of E-selectin expression but were found to be hyporesponsive to stimulation with the specific TLR2 ligands macrophage activating lipopeptide-2, PAM2-Cys, and Lip19; this was observed to be attributable to downregulation of TLR2 transcription and protein expression. We found that laminar flow induced SP1 serine phosphorylation by protein kinase CK2 and thereby blocked SP1 binding to the TLR2 promoter, which is required for TLR2 expression. This regulatory mechanism also blocked lipopolysaccharide- and tumor necrosis factor-induced TLR2 upregulation in HCAECs and could be important for suppression of other flow-sensitive endothelial proteins. These results extend the role of flow in controlling endothelial responsiveness. Given the current evidence that TLRs are proatherogenic, flow suppression of TLR2 expression may be atheroprotective.
Key words: endothelial cell • shear stress • innate immunity • atherosclerosis • TLR2 • TLR4
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