In:
Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 32, No. 11 ( 2012-11), p. 2751-2760
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
1079-5642
,
1524-4636
DOI:
10.1161/ATVBAHA.112.300302
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2012
detail.hit.zdb_id:
1494427-3
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