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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...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2016
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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. |
format | Online Article Text |
id | pubmed-5037674 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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