title: PPARγ agonist rosiglitazone ameliorates LPS-induced inflammation in vascular smooth muscle cells via the TLR4/TRIF/IRF3/IP-10 signaling pathway.
abstract: The activation of toll-like receptor 4 (TLR4) by lipopolysaccharide (LPS) can induce inflammation that are one of key etiological conditions for the development of many chronic inflammatory diseases including atherosclerosis and diabetes. Peroxisome proliferator-activated receptor γ (PPARγ) agonists play a crucial role in improving glucose and lipid homeostasis in the development of cardiovascular diseases. Evidence is growing that benefits of PPARγ agonists may also be derived from the anti-inflammatory and anti-atherosclerotic properties of these agents. However, the role of rosiglitazone in regulating LPS-induced vascular inflammation has yet to be fully elucidated. The current study demonstrated that rosiglitazone exerted a potent anti-inflammatory action via decreasing interleukin-18 (IL-18), tissue inhibitor of metalloproteinase-1 (TIMP-1), TLR4 and increasing PPARγ in LPS-induced VSMCs. Furthermore, treatment of VSMCs with the TLR4 blocker or TLR4 small-interfering RNA presented that the regulatory effects of rosiglitazone on LPS-mediated inflammation in VSMCs were dependent on TLR4. Interestingly, the results indicated that beneficial effects of rosiglitazone on LPS-induced inflammation in VSMCs were mediated via interference of TLR4 and its downstream signaling components including Toll-interleukin-1 (IL-1) receptor domain-containing adaptor inducing interferon-β (TRIF), interferon regulatory factor 3 (IRF3) and interferon-gamma inducible protein 10 (IP-10). In summary, PPARγ agonist rosiglitazone exerts anti-inflammatory property by antagonizing LPS-mediated inflammation in VSMCs. More importantly, the regulation of the TRIF-dependent TLR4 signaling pathway (TLR4/TRIF/ IRF3/IP-10) provides new insight to understand the mode of action of rosiglitazone for its anti-inflammatory effects.
authors.affiliation: Scientific Research Center, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an 710004, PR China. jiyuanyuan1234@163.com
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Ji
authors.forename: Juntian
authors.initials: J
authors.lastname: Liu
authors.forename: Zhidong
authors.initials: Z
authors.lastname: Wang
authors.forename: Zongfang
authors.initials: Z
authors.lastname: Li
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents; D002478:Cells, Cultured; D054357:Chemokine CXCL10 / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D007249:Inflammation / Q000276:immunology; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D020382:Interleukin-18 / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology* / Q000494:pharmacology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D047495:PPAR gamma / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D045162:Thiazolidinediones / Q000494:pharmacology*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D000893:Anti-Inflammatory Agents; D054357:Chemokine CXCL10; C091326:Cxcl10 protein, rat; D050838:Interferon Regulatory Factor-3; D020382:Interleukin-18; D008070:Lipopolysaccharides; D047495:PPAR gamma; D034741:RNA, Small Interfering; D045162:Thiazolidinediones; C523075:Ticam1 protein, rat; D019715:Tissue Inhibitor of Metalloproteinase-1; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D000077154:Rosiglitazone