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Int. J. Mol. Sci. 2016, 17(9), 1394; doi:10.3390/ijms17091394

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

1
Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan 35053, Taiwan
2
Graduate Institutes of Life Sciences, National Defense Medical Center, Neihu, Taipei 11490, Taiwan
3
Division of Cardiovascular Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Neihu, Taipei 11490, Taiwan
4
Division of Cardiology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Neihu, Taipei 11490, Taiwan
5
Institute of Molecular Medicine, National Tsing Hua University, Hsinchu 30013, Taiwan
6
Division of Nephrology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Neihu, Taipei 11490, Taiwan
7
Department of Biochemistry, National Defense Medical Center, Neihu, Taipei 11490, Taiwan
8
Graduate Institute of Basic Medical Science, China Medical University, Taichung 40402, Taiwan
*
Author to whom correspondence should be addressed.
Academic Editor: Atsushi Matsuzawa
Received: 1 July 2016 / Revised: 11 August 2016 / Accepted: 17 August 2016 / Published: 24 August 2016
(This article belongs to the Special Issue Kinase Signal Transduction)
View Full-Text   |   Download PDF [5540 KB, uploaded 26 August 2016]   |  

Abstract

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. View Full-Text
Keywords: Toll-like receptor 4; vascular smooth muscle cells; cAMP response element binding protein; Interleukin 6; migration Toll-like receptor 4; vascular smooth muscle cells; cAMP response element binding protein; Interleukin 6; migration
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MDPI and ACS Style

Lee, G.-L.; Wu, J.-Y.; Tsai, C.-S.; Lin, C.-Y.; Tsai, Y.-T.; Lin, C.-S.; Wang, Y.-F.; Yet, S.-F.; Hsu, Y.-J.; Kuo, C.-C. TLR4-Activated MAPK-IL-6 Axis Regulates Vascular Smooth Muscle Cell Function. Int. J. Mol. Sci. 2016, 17, 1394.

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