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.

Vanadium Derivative Exposure Promotes Functional Alterations of VSMCs and Consequent Atherosclerosis via ROS/p38/NF-κB-Mediated IL-6 Production

“…Notably, these NaVO 3 -induced atherosclerotic pathologies in ApoE −/− mice were prevented by NAC treatment, indicating that ROS is required for NaVO 3 -driven atherosclerosis. Our results further show that VOSO 4 and NaVO 3 promote phenotypic transitions of VSMCs from the quiescent contractile state to the active synthetic state and VSMC proliferation and migration, which has been implicated in deleterious consequences of atherosclerosis [3,25,26,29]. The present study provides experimental evidence that vanadium salts, VOSO 4 and NaVO 3 , drive VSMC pathological responses by inducing ROS production and thereby activating p38/NF-κB signaling.…”

“…The pleiotropic cytokine IL-6 is a proatherogenic factor that is increased in atherosclerotic mouse plasma and in VSMCs in response to atherosclerotic stimulators. Accumulating evidence suggests IL-6 is implicated in the progression of atherosclerosis and plays a key role in inducing VSMC migration and proliferation [25,26,38,39]. Our findings indicate that NaVO 3 triggers VSMC migration and proliferation through ROS-mediated IL-6 production.…”

“…This initiates with endothelial injury followed by immune and proinflammatory cell accumulation, lipid deposition, and progressive inflammatory responses [4,23,24]. Further, the inflammatory responses in the microenvironment of atherosclerotic lesions drive medial smooth muscle cell migration and proliferation into the intima, consequently causing plaque formation, which is a key event in the pathophysiology of atherosclerosis [3,[25][26][27]. Vascular smooth muscle cells (VSMCs) reside in the media of normal blood vessels, where they are quiescent and assume a contractile phenotype.…”

Lipopolysaccharide potentiates platelet responses via toll-like receptor 4-stimulated Akt-Erk-PLA2 signalling

“…TBK-1, IRAK-1, JNKs, MAPK, TRAF3, TRAF6, IRF-3, Ikk-I, IκB-α, NK-κB) that are present in platelets [ 7 , 19 , 20 ]. In vascular smooth muscle, LPS- mediated signalling promotes activation of the mitogen-activated kinases (MAPKs) p38, ERK1/2 and JNK1/2 and also the phosphoinositide- 3 kinase (PI3-kinase) dependent signalling [ 21 ]. Furthermore, Brown and McIntyre showed that in platelets, MyD88, TRAF6, JNK and AKT are required in IL-1β production stimulated by LPS [ 22 ].…”

MAPK/p38 regulation of cytoskeleton rearrangement accelerates induction of macrophage activation by TLR4, but not TLR3

“…PD98059 and SP600125, MAPK/ERK and JNK signaling pathway inhibitors, respectively, exerted no effect on cytoskeleton rearrangement leading to cytokine production. In previous studies, the MAPK signaling pathway was found to participate in tubulin and/or actin polymerization, regulating migration of vascular smooth muscle cells ( 34 ), podocyte response to ox-LDL ( 35 ) and hepatocellular cholestasis induced by oxidative stress ( 36 ). In addition, it was demonstrated that p38 phosphorylation, but not p65 phosphorylation, was ablated following VCR priming and LPS stimulation compared with LPS alone.…”