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TLR4-Activated MAPK-IL-6 Axis Regulates Vascular Smooth Muscle Cell Function

Migration of vascular smooth muscle cells (VSMCs) into the intima is considered to be a vital event in the pathophysiology of atherosclerosis. Despite substantial evidence supporting the pathogenic role of Toll-like receptor 4 (TLR4) in the progression of atherogenesis, its function in the regulatio...

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Autores principales: Lee, Guan-Lin, Wu, Jing-Yiing, Tsai, Chien-Sung, Lin, Chih-Yuan, Tsai, Yi-Ting, Lin, Chin-Sheng, Wang, Yi-Fu, Yet, Shaw-Fang, Hsu, Yu-Juei, Kuo, Cheng-Chin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5037674/
https://www.ncbi.nlm.nih.gov/pubmed/27563891
http://dx.doi.org/10.3390/ijms17091394
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author Lee, Guan-Lin
Wu, Jing-Yiing
Tsai, Chien-Sung
Lin, Chih-Yuan
Tsai, Yi-Ting
Lin, Chin-Sheng
Wang, Yi-Fu
Yet, Shaw-Fang
Hsu, Yu-Juei
Kuo, Cheng-Chin
author_facet Lee, Guan-Lin
Wu, Jing-Yiing
Tsai, Chien-Sung
Lin, Chih-Yuan
Tsai, Yi-Ting
Lin, Chin-Sheng
Wang, Yi-Fu
Yet, Shaw-Fang
Hsu, Yu-Juei
Kuo, Cheng-Chin
author_sort Lee, Guan-Lin
collection PubMed
description Migration of vascular smooth muscle cells (VSMCs) into the intima is considered to be a vital event in the pathophysiology of atherosclerosis. Despite substantial evidence supporting the pathogenic role of Toll-like receptor 4 (TLR4) in the progression of atherogenesis, its function in the regulation of VSMC migration remains unclear. The goal of the present study was to elucidate the mechanism by which TLR4 regulates VSMC migration. Inhibitor experiments revealed that TLR4-induced IL-6 secretion and VSMC migration were mediated via the concerted actions of MyD88 and TRIF on the activation of p38 MAPK and ERK1/2 signaling. Neutralizing anti-IL-6 antibodies abrogated TLR4-driven VSMC migration and F-actin polymerization. Blockade of p38 MAPK or ERK1/2 signaling cascade inhibited TLR4 agonist-mediated activation of cAMP response element binding protein (CREB). Moreover, siRNA-mediated suppression of CREB production repressed TLR4-induced IL-6 production and VSMC migration. Rac-1 inhibitor suppressed TLR4-driven VSMC migration but not IL-6 production. Importantly, the serum level of IL-6 and TLR4 endogenous ligand HMGB1 was significantly higher in patients with coronary artery diseases (CAD) than in healthy subjects. Serum HMGB1 level was positively correlated with serum IL-6 level in CAD patients. The expression of both HMGB1 and IL-6 was clearly detected in the atherosclerotic tissue of the CAD patients. Additionally, there was a positive association between p-CREB and HMGB1 in mouse atherosclerotic tissue. Based on our findings, we concluded that, upon ligand binding, TLR4 activates p38 MAPK and ERK1/2 signaling through MyD88 and TRIF in VSMCs. These signaling pathways subsequently coordinate an additive augmentation of CREB-driven IL-6 production, which in turn triggers Rac-1-mediated actin cytoskeleton to promote VSMC migration.
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spelling pubmed-50376742016-09-29 TLR4-Activated MAPK-IL-6 Axis Regulates Vascular Smooth Muscle Cell Function Lee, Guan-Lin Wu, Jing-Yiing Tsai, Chien-Sung Lin, Chih-Yuan Tsai, Yi-Ting Lin, Chin-Sheng Wang, Yi-Fu Yet, Shaw-Fang Hsu, Yu-Juei Kuo, Cheng-Chin Int J Mol Sci Article Migration of vascular smooth muscle cells (VSMCs) into the intima is considered to be a vital event in the pathophysiology of atherosclerosis. Despite substantial evidence supporting the pathogenic role of Toll-like receptor 4 (TLR4) in the progression of atherogenesis, its function in the regulation of VSMC migration remains unclear. The goal of the present study was to elucidate the mechanism by which TLR4 regulates VSMC migration. Inhibitor experiments revealed that TLR4-induced IL-6 secretion and VSMC migration were mediated via the concerted actions of MyD88 and TRIF on the activation of p38 MAPK and ERK1/2 signaling. Neutralizing anti-IL-6 antibodies abrogated TLR4-driven VSMC migration and F-actin polymerization. Blockade of p38 MAPK or ERK1/2 signaling cascade inhibited TLR4 agonist-mediated activation of cAMP response element binding protein (CREB). Moreover, siRNA-mediated suppression of CREB production repressed TLR4-induced IL-6 production and VSMC migration. Rac-1 inhibitor suppressed TLR4-driven VSMC migration but not IL-6 production. Importantly, the serum level of IL-6 and TLR4 endogenous ligand HMGB1 was significantly higher in patients with coronary artery diseases (CAD) than in healthy subjects. Serum HMGB1 level was positively correlated with serum IL-6 level in CAD patients. The expression of both HMGB1 and IL-6 was clearly detected in the atherosclerotic tissue of the CAD patients. Additionally, there was a positive association between p-CREB and HMGB1 in mouse atherosclerotic tissue. Based on our findings, we concluded that, upon ligand binding, TLR4 activates p38 MAPK and ERK1/2 signaling through MyD88 and TRIF in VSMCs. These signaling pathways subsequently coordinate an additive augmentation of CREB-driven IL-6 production, which in turn triggers Rac-1-mediated actin cytoskeleton to promote VSMC migration. MDPI 2016-08-24 /pmc/articles/PMC5037674/ /pubmed/27563891 http://dx.doi.org/10.3390/ijms17091394 Text en © 2016 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC-BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Lee, Guan-Lin
Wu, Jing-Yiing
Tsai, Chien-Sung
Lin, Chih-Yuan
Tsai, Yi-Ting
Lin, Chin-Sheng
Wang, Yi-Fu
Yet, Shaw-Fang
Hsu, Yu-Juei
Kuo, Cheng-Chin
TLR4-Activated MAPK-IL-6 Axis Regulates Vascular Smooth Muscle Cell Function
title TLR4-Activated MAPK-IL-6 Axis Regulates Vascular Smooth Muscle Cell Function
title_full TLR4-Activated MAPK-IL-6 Axis Regulates Vascular Smooth Muscle Cell Function
title_fullStr TLR4-Activated MAPK-IL-6 Axis Regulates Vascular Smooth Muscle Cell Function
title_full_unstemmed TLR4-Activated MAPK-IL-6 Axis Regulates Vascular Smooth Muscle Cell Function
title_short TLR4-Activated MAPK-IL-6 Axis Regulates Vascular Smooth Muscle Cell Function
title_sort tlr4-activated mapk-il-6 axis regulates vascular smooth muscle cell function
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5037674/
https://www.ncbi.nlm.nih.gov/pubmed/27563891
http://dx.doi.org/10.3390/ijms17091394
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