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Vascular Biology

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

Guan-Lin Lee, Ya-Wei Chang, Jing-Yiing Wu, Meng-Ling Wu, Kenneth K. Wu, Shaw-Fang Yet, Cheng-Chin Kuo
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https://doi.org/10.1161/ATVBAHA.112.300302
Arteriosclerosis, Thrombosis, and Vascular Biology. 2012;ATVBAHA.112.300302
Originally published September 20, 2012
Guan-Lin Lee
From the Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan (G.-L.L., Y.-W.C., J.-Y. W., M.-L.W., K.K.W., S.-F.Y., C.-C.K.); Graduate Institutes of Life Sciences and Biochemistry, National Defense Medical Center, Taipei, Taiwan (G.-L.L., Y.-W.C.); Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan (J.-Y. W.); and Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan (S.-F.Y., C.-C.K.).
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Ya-Wei Chang
From the Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan (G.-L.L., Y.-W.C., J.-Y. W., M.-L.W., K.K.W., S.-F.Y., C.-C.K.); Graduate Institutes of Life Sciences and Biochemistry, National Defense Medical Center, Taipei, Taiwan (G.-L.L., Y.-W.C.); Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan (J.-Y. W.); and Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan (S.-F.Y., C.-C.K.).
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Jing-Yiing Wu
From the Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan (G.-L.L., Y.-W.C., J.-Y. W., M.-L.W., K.K.W., S.-F.Y., C.-C.K.); Graduate Institutes of Life Sciences and Biochemistry, National Defense Medical Center, Taipei, Taiwan (G.-L.L., Y.-W.C.); Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan (J.-Y. W.); and Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan (S.-F.Y., C.-C.K.).
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Meng-Ling Wu
From the Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan (G.-L.L., Y.-W.C., J.-Y. W., M.-L.W., K.K.W., S.-F.Y., C.-C.K.); Graduate Institutes of Life Sciences and Biochemistry, National Defense Medical Center, Taipei, Taiwan (G.-L.L., Y.-W.C.); Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan (J.-Y. W.); and Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan (S.-F.Y., C.-C.K.).
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Kenneth K. Wu
From the Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan (G.-L.L., Y.-W.C., J.-Y. W., M.-L.W., K.K.W., S.-F.Y., C.-C.K.); Graduate Institutes of Life Sciences and Biochemistry, National Defense Medical Center, Taipei, Taiwan (G.-L.L., Y.-W.C.); Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan (J.-Y. W.); and Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan (S.-F.Y., C.-C.K.).
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Shaw-Fang Yet
From the Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan (G.-L.L., Y.-W.C., J.-Y. W., M.-L.W., K.K.W., S.-F.Y., C.-C.K.); Graduate Institutes of Life Sciences and Biochemistry, National Defense Medical Center, Taipei, Taiwan (G.-L.L., Y.-W.C.); Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan (J.-Y. W.); and Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan (S.-F.Y., C.-C.K.).
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Cheng-Chin Kuo
From the Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan (G.-L.L., Y.-W.C., J.-Y. W., M.-L.W., K.K.W., S.-F.Y., C.-C.K.); Graduate Institutes of Life Sciences and Biochemistry, National Defense Medical Center, Taipei, Taiwan (G.-L.L., Y.-W.C.); Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan (J.-Y. W.); and Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan (S.-F.Y., C.-C.K.).
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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.
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    TLR 2 Induces Vascular Smooth Muscle Cell Migration Through cAMP Response Element−Binding Protein−Mediated Interleukin-6 Production
    Guan-Lin Lee, Ya-Wei Chang, Jing-Yiing Wu, Meng-Ling Wu, Kenneth K. Wu, Shaw-Fang Yet and Cheng-Chin Kuo
    Arteriosclerosis, Thrombosis, and Vascular Biology. 2012;ATVBAHA.112.300302, originally published September 20, 2012
    https://doi.org/10.1161/ATVBAHA.112.300302

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    TLR 2 Induces Vascular Smooth Muscle Cell Migration Through cAMP Response Element−Binding Protein−Mediated Interleukin-6 Production
    Guan-Lin Lee, Ya-Wei Chang, Jing-Yiing Wu, Meng-Ling Wu, Kenneth K. Wu, Shaw-Fang Yet and Cheng-Chin Kuo
    Arteriosclerosis, Thrombosis, and Vascular Biology. 2012;ATVBAHA.112.300302, originally published September 20, 2012
    https://doi.org/10.1161/ATVBAHA.112.300302
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