Role of Toll-like receptor 4/NF-kappaB pathway in monocyte-endothelial adhesion induced by low shear stress and ox-LDL.
TLR4 plays an important role in atherosclerosis, but little is known about the precise mechanism. Herein, we investigated the role of TLR4/NF-kappaB signaling pathway in monocyte-endothelial adhesion induced by low shear stress and Ox-LDL. We found that low shear stress up-regulated TLR4 expression in endothelial cells, and that ox-LDL exerted an obvious synergistic action as revealed by RT-PCR and Western blotting analysis. Low shear stress also significantly up-regulated IL-8 expression in endothelial cells. Meanwhile, NF-kappaB activity and the adhesion force of monocytes were increased, and there was a synergetic action of ox-LDL. However, following transfection with a functional mutant of TLR4 (C3H/HeJ, TLR4 Dicd) or addition of anti-human TLR4 mAb, IL-8 expression was obviously decreased, NF-kappaB activity in cells remarkably inhibited, and the adhesion force of monocyte significantly reduced. Nevertheless, anti-human TLR2 mAb had no similar effects. These findings suggest that TLR4 may be involved in the early stages of atherosclerosis, associating ox-LDL, inflammation/infection, and low shear stress. Therefore, TLR4 is expected to be a new target for preventing and treating atherosclerosis.
Yang
Qing-Wu
QW
Department of Neurology, Daping Hospital, Third Military Medical University, Chongqing, China. yangqwmlys@hotmail.com
Mou
Lin
L
Lv
Feng-Lin
FL
Wang
Jing-Zhou
JZ
Wang
Lin
L
Zhou
Hong-Jie
HJ
Gao
Dong
D
D001161:Arteriosclerosis / Q000503:physiopathology; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D007231:Infant, Newborn; D016209:Interleukin-8 / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000378:metabolism / Q000502:physiology*; D009000:Monocytes / Q000166:cytology*; D016328:NF-kappa B / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D013314:Stress, Mechanical; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D016209:Interleukin-8; D008077:Lipoproteins, LDL; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D011956:Receptors, Cell Surface; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; C099252:oxidized low density lipoprotein