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.

Chondroprotection of PPARα activation by WY14643 via autophagy involving Akt and ERK in LPS‐treated mouse chondrocytes and osteoarthritis model

“…Similarly, WY14643 inhibits LPS-induced inflammation in synovial fibroblasts via NF-kB pathway 32 and inhibits the inflammatory and destructive responses in human OA cartilage explants. 15 Hence, WY14643 may also ameliorate OA symptoms like other PPARα agonists.…”

Peroxisome Proliferator-Activated Receptors as a Therapeutic Target in Asthma

“…PPARs inhibit many transcription factors possessing a proinflammatory action: NF-κB, AP-1, protein C/EBP (CCAAT/enhancer-binding protein), and signal transducers and activators of transcription (STAT). The relationships between PPARs and NF-κB are of special interest [5,6,37,45,46].…”

“…The anti-inflammatory properties of PPARs are mainly achieved by inhibiting nuclear factor-kappa B (NF-κB) which, in turn, is the proinflammatory nuclear transcription factor. The relationship between PPARs and NF-κB is an important object of the current studies, since it may serve as a target for development of strategies to control the activity of the inflammatory process [5,6]. The interactions between PPARs, NF-κB, and toll-like receptors (TLRs) are of great interest [7].…”

Role of low-grade inflammation in osteoarthritis

“…Correlations between pain scores and radiographic features were seen with both serum and synovial fluid LPS levels. In a separate study [30■], an agonist of the nuclear receptor peroxisome proliferator-activated receptor-alpha (PPAR-α) was shown to attenuate synovial fibroblast LPS responses, pointing to potential therapeutics. However, whether the relationship between LPS and osteoarthritis severity is directly mediated by TLR-4 interaction remains to be seen.…”