TLR 2 Induces Vascular Smooth Muscle Cell Migration Through cAMP Response Element−Binding Protein−Mediated Interleukin-6 Production

Abstract
Objective—Migration of vascular smooth muscle cells (VSMCs) from the media into intima contributes to the development of atherosclerosis. Gene deletion experiments implicate a role for toll-like receptor 2 (TLR2) in atherogenesis. However, the underlying mechanisms remain unclear. We postulate that TLR2 promotes VSMC migration by enhancing interleukin (IL)-6 production.
Methods and Results—Migration assays revealed that TLR2 agonists promoted VSMC migration but not cell proliferation or viability. TLR2 deficiency or inhibition of TLR2 signaling with anti-TLR2 antibody suppressed TLR2 agonist–induced VSMC migration and IL-6 production, which was mediated via p38 mitogen-associated protein kinase and extracellular signal–regulated kinase 1/2 signaling pathways. Neutralizing anti–IL-6 antibodies impaired TLR2-mediated VSMC migration and formation of filamentous actin fiber and lamellipodia. Blockade of p38 mitogen-associated protein kinase or extracellular signal–regulated kinase 1/2 activation inhibited TLR2 agonist pam3CSK4-induced phosphorylation of cAMP response element–binding protein, which regulates IL-6 promoter activity through the cAMP response element site. Moreover, cAMP response element–binding protein small interfering RNA inhibited pam3CSK4-induced IL-6 production and VSMC migration. Additionally, Rac1 small interfering RNA inhibited pam3CSK4-induced VSMC migration but not IL-6 production.
Conclusion—Our results suggest that on ligand binding, TLR2 activates p38 mitogen-associated protein kinase and extracellular signal–regulated kinase 1/2 signaling in VSMCs. These signaling pathways act in concert to activate cAMP response element–binding protein and subsequent IL-6 production, which in turn promotes VSMC migration via Rac1-mediated actin cytoskeletal reorganization.
- toll-like receptor 2
- vascular smooth muscle cells
- cAMP response element–binding protein
- interleukin-6
- migration
- Received October 21, 2012.
- Accepted August 31, 2012.
- © 2012 American Heart Association, Inc.
Current Issue
Article Tools
- TLR 2 Induces Vascular Smooth Muscle Cell Migration Through cAMP Response Element−Binding Protein−Mediated Interleukin-6 ProductionGuan-Lin Lee, Ya-Wei Chang, Jing-Yiing Wu, Meng-Ling Wu, Kenneth K. Wu, Shaw-Fang Yet and Cheng-Chin KuoArteriosclerosis, Thrombosis, and Vascular Biology. 2012;ATVBAHA.112.300302, originally published September 20, 2012https://doi.org/10.1161/ATVBAHA.112.300302
Citation Manager Formats
Share this Article
- TLR 2 Induces Vascular Smooth Muscle Cell Migration Through cAMP Response Element−Binding Protein−Mediated Interleukin-6 ProductionGuan-Lin Lee, Ya-Wei Chang, Jing-Yiing Wu, Meng-Ling Wu, Kenneth K. Wu, Shaw-Fang Yet and Cheng-Chin KuoArteriosclerosis, Thrombosis, and Vascular Biology. 2012;ATVBAHA.112.300302, originally published September 20, 2012https://doi.org/10.1161/ATVBAHA.112.300302