title: TLR4-Activated MAPK-IL-6 Axis Regulates Vascular Smooth Muscle Cell Function.
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.
authors: Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan 35053, Taiwan. lgl0311@gmail.com.|Graduate Institutes of Life Sciences, National Defense Medical Center, Neihu, Taipei 11490, Taiwan. lgl0311@gmail.com.
authors: Guan-Lin
authors: GL
authors: Lee
authors: Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan 35053, Taiwan. jywu@nhri.org.tw.
authors: Jing-Yiing
authors: JY
authors: Wu
authors: Division of Cardiovascular Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Neihu, Taipei 11490, Taiwan. sung1500@ndmctsgh.edu.tw.
authors: Chien-Sung
authors: CS
authors: Tsai
authors: Division of Cardiovascular Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Neihu, Taipei 11490, Taiwan. linrock@ms26.hinet.net.
authors: Chih-Yuan
authors: CY
authors: Lin
authors: Division of Cardiovascular Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Neihu, Taipei 11490, Taiwan. cvsallen@ndmctsgh.edu.tw.
authors: Yi-Ting
authors: YT
authors: Tsai
authors: Division of Cardiology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Neihu, Taipei 11490, Taiwan. littlelincs@gmail.com.
authors: Chin-Sheng
authors: CS
authors: Lin
authors: Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan 35053, Taiwan. ariesw@nhri.org.tw.|Institute of Molecular Medicine, National Tsing Hua University, Hsinchu 30013, Taiwan. ariesw@nhri.org.tw.
authors: Yi-Fu
authors: YF
authors: Wang
authors: Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan 35053, Taiwan. syet@nhri.org.tw.
authors: Shaw-Fang
authors: SF
authors: Yet
authors: Division of Nephrology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Neihu, Taipei 11490, Taiwan. yujuei@mail2000.com.tw.|Department of Biochemistry, National Defense Medical Center, Neihu, Taipei 11490, Taiwan. yujuei@mail2000.com.tw.
authors: Yu-Juei
authors: YJ
authors: Hsu
authors: Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan 35053, Taiwan. kuocc@nhri.org.tw.|Graduate Institutes of Life Sciences, National Defense Medical Center, Neihu, Taipei 11490, Taiwan. kuocc@nhri.org.tw.|Institute of Molecular Medicine, National Tsing Hua University, Hsinchu 30013, Taiwan. kuocc@nhri.org.tw.|Graduate Institute of Basic Medical Science, China Medical University, Taichung 40402, Taiwan. kuocc@nhri.org.tw.
authors: Cheng-Chin
authors: CC
authors: Kuo
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000818:Animals; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D017362:Cyclic AMP Response Element-Binding Protein; D016753:Interleukin-10; D018664:Interleukin-12; D015850:Interleukin-6; D053594:Myeloid Differentiation Factor 88; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; C476286:Ticam1 protein, mouse
keywords: Interleukin 6; Toll-like receptor 4; cAMP response element binding protein; migration; vascular smooth muscle cells