TLR4 induces CREB-mediated IL-6 production via upregulation of F-spondin to promote vascular smooth muscle cell migration.
Toll-like receptor 4 (TLR4) is important in promoting inflammation and vascular smooth muscle cell (VSMC) migration, both of which contribute to atherosclerosis development and progression. But the mechanism underlying the regulation of TLR4 in VSMC migration remains unclear. Stimulation of VSMCs with LPS increased the cellular level of F-spondin which is associated with the regulation of proinflammatory cytokine production. The LPS-induced F-spondin expression depended on TLR4-mediated PI3K/Akt pathway. Suppression of F-spondin level by siRNA inhibited not only F-spondin expression but also LPS-induced phosphorylation of cAMP response element binding protein (CREB) and IL-6 expression, VSMC migration and proliferation as well as MMP9 expression. Moreover, suppression of CREB level by siRNA inhibited TLR4-induced IL-6 production and VSMC migration. Inhibition of F-spondin siRNA on LPS-induced migration was restored by addition of exogenous recombinant mouse IL-6. We conclude that upon ligand binding, TLR4 activates PI3K/Akt signaling to induce F-spondin expression, subsequently control CREB-mediated IL-6 production to promote VSMC migration. These findings provide vital insights into the essential role of F-spondin in VSMC function and will be valuable for developing new therapeutic strategies against atherosclerosis.
Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan; Graduate Institutes of Life Sciences, National Defense Medical Center, Taipei, Taiwan.
Guan-Lin
GL
Lee
Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan.
Jing-Yiing
JY
Wu
Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan; Graduate Institutes of Life Sciences, National Defense Medical Center, Taipei, Taiwan.
Chang-Ching
CC
Yeh
Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan; Graduate Institutes of Life Sciences, National Defense Medical Center, Taipei, Taiwan; Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan. Electronic address: kuocc@nhri.org.tw.
Cheng-Chin
CC
Kuo
D000818:Animals; D050882:CREB-Binding Protein / Q000378:metabolism*; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D002478:Cells, Cultured; D015850:Interleukin-6 / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000502:physiology*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D015854:Up-Regulation / Q000502:physiology
D015850:Interleukin-6; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C577686:interleukin-6, mouse; D050882:CREB-Binding Protein; C494364:Crebbp protein, mouse
CREB; F-spondin; IL-6; TLR4; VSMC migration