Modulation of LPS-mediated inflammation by fenofibrate via the TRIF-dependent TLR4 signaling pathway in vascular smooth muscle cells.
Lipopolysaccharide (LPS) induced-vascular inflammation plays a central role in vasculitis and atherosclerosis. The stimulation of toll-like receptor 4 (TLR4) by LPS elicits the release of major proinflammatory cytokines that aggravates cardiovascular disorders. Peroxisome proliferator- activated receptor alpha (PPARalpha) agonists have been shown to reduce cardiovascular events by controlling lipid metabolism as well as inflammation. However, the role of PPARalpha agonist fenofibrate in modulating LPS-mediated inflammatory responses in vascular smooth muscle cells (VSMCs) remains elusive. The present study demonstrated that fenofibrate exerted a potent anti-inflammatory action through reducing interleckin-1(IL-18), tissue inhibitor of metalloproteinase-1(TIMP-1), TLR4 and enhancing PPARalpha in LPS-stimulated VSMCs. Additionally, treatment of VSMCs with the TLR4 inhibition or TLR4 small-interfering RNA illustrated that the modulatory effects of fenofibrate on LPS-mediated inflammatory responses in VSMCs were reliant on TLR4. Especially, the results suggested that beneficial effects of fenofibrate on LPS-stimulated inflammatory responses in VSMCs were mediated through interference of TLR4 and its downstream signaling components such as Toll-interleckin-1(IL-1) receptor domain- containing adaptor inducing interferon-beta (TRIF), interferon regulatory factor 3 (IRF3) and interferon-gamma inducible protein 10 (IP-10). In conclusion, PPARalpha agonist fenofibrate exerts anti-inflammatory property by antagonizing LPS-mediated inflammatory responses in VSMCs. More importantly, the modulation of the TRIF-dependent signaling pathway (TLR4/TRIF/IRF3/IP-10) might be a useful and novel anti-inflammatory strategy of fenofibrate.
Ji
Yuanyuan
Y
Scientific Research Center, School of Medicine, Xi'an Jiaotong University, Xi'an 710004, China. jiyuanyuan1234@163.com
Wang
Zhidong
Z
Li
Zongfang
Z
Liu
Juntian
J
D033942:Adaptor Proteins, Vesicular Transport / Q000276:immunology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D011345:Fenofibrate / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D020382:Interleukin-18 / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000276:immunology; D047493:PPAR alpha / Q000819:agonists* / Q000235:genetics / Q000276:immunology; D048068:PPAR-beta / Q000235:genetics / Q000276:immunology; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology*
D033942:Adaptor Proteins, Vesicular Transport; D000893:Anti-Inflammatory Agents; D020382:Interleukin-18; D008070:Lipopolysaccharides; D047493:PPAR alpha; D048068:PPAR-beta; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C523075:Ticam1 protein, rat; D019715:Tissue Inhibitor of Metalloproteinase-1; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D011345:Fenofibrate