title: PPAR-α Agonist WY-14643 Inhibits LPS-Induced Inflammation in Synovial Fibroblasts via NF-kB Pathway.
abstract: Osteoarthritis (OA), the most prevalent form of arthritis that results from breakdown of joint cartilage and underlying bone, has been viewed as a chronic condition manifested by persistence of inflammatory responses and infiltration of lymphocytes. Regulation of the inflammatory responses in synovial fibroblasts might be useful to prevent the development and deterioration of osteoarthritis. WY-14643, a potent peroxisome proliferator activator receptor-α (PPAR-α) agonist, has been described to beneficially regulate inflammation in many mammalian cells. Here, we investigate the potential anti-inflammatory role of WY-14643 in lipopolysaccharide (LPS)-induced synovial fibroblasts. WY-14643 greatly inhibited the production of NO and PGE2 induced by LPS. In addition, the mRNA expression of intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), endothelin-1 (ET-1), and tissue factor (TF) was significantly suppressed by WY-14643, as well as the secretion of pro-inflammatory cytokines including interleukin-6 (IL-6), IL-1β, tumor necrosis factor-α (TNF-α), and monocyte chemotactic protein-1 (MCP-1). Furthermore, the transcription activity and nuclear translocation of NF-kB were found to be markedly decreased by WY-14643, while the phosphorylation of IkB was enhanced, indicating that the anti-inflammatory role of WY-14643 was meditated by NF-kB-dependent pathway. The application of WY-14643 failed to carry out its anti-inflammatory function in PPAR-α silenced cells, suggesting the role of PPAR-α. These findings may facilitate further studies investigating the translation of pharmacological PPAR-α activation into clinical therapy of OA.
authors.affiliation: Department of Orthopedic Surgery, Yijishan Hospital, Wannan Medical College, Wuhu, Anhui, People's Republic of China. xuhg@medmail.com.cn.
authors.forename: Degang
authors.initials: D
authors.lastname: Huang
authors.affiliation: Department of Orthopedic Surgery, Yijishan Hospital, Wannan Medical College, Wuhu, Anhui, People's Republic of China.
authors.forename: Quanlai
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: Department of Orthopedic Surgery, Yijishan Hospital, Wannan Medical College, Wuhu, Anhui, People's Republic of China.
authors.forename: Hongfei
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Orthopedic Surgery, Yijishan Hospital, Wannan Medical College, Wuhu, Anhui, People's Republic of China.
authors.forename: Yongjie
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of Orthopedic Surgery, Yijishan Hospital, Wannan Medical College, Wuhu, Anhui, People's Republic of China. xuhg@medmail.com.
authors.forename: Hongguang
authors.initials: H
authors.lastname: Xu
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D017746:Joint Capsule / Q000166:cytology; D008070:Lipopolysaccharides / Q000633:toxicity; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D010003:Osteoarthritis / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D019332:Endothelin-1; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D016328:NF-kappa B; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011743:Pyrimidines; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D009569:Nitric Oxide; C006253:pirinixic acid; D015232:Dinoprostone
keywords: Inflammation; NF-kB; Osteoarthritis; Synovial fibroblasts; WY-14643