PPAR-γ alleviates the inflammatory response in TNF-α-induced fibroblast-like synoviocytes by binding to p53 in rheumatoid arthritis

Rheumatoid arthritis (RA) is characterized by synovial inflammation, synoviocyte expansion and damage to cartilage and bone. We recently reported that peroxisome proliferator-activated receptor (PPAR)-gamma inhibited the proliferation and activation of fibroblast-like synoviocytes (FLS), and was downregulated in RA synovial. In this study we investigated the role of PPAR-gamma in RA and the underlying mechanisms. Adjuvant-induced arthritis (AIA) was induced in rats; from D15, AIA rats were orally administered pioglitazone (30 mg.kg(-1).d(-1)) or rosiglitazone (4 mg.kg(-1).d(-1)) for 14 days. Collagen-induced arthritis (CIA) was induced in wild-type and Ppar-gamma(+/-) mice. We showed that the expression of PPAR-gamma was significantly reduced, whereas that of TNF-alpha was markedly increased in human RA FLS. In CIA mice, knockdown of PPAR-gamma expression (Ppar-gamma(+/-)) aggravated the ankle inflammation. Similarly, T0070907 (a PPAR-gamma antagonist) or si-PPAR-gamma promoted the activation and inflammation of TNF-alpha-induced FLS in vitro. On the contrary, administration of PPAR-gamma agonist pioglitazone or rosiglitazone, or injection of ad-Ppar-gamma into the ankle of AIA rat in vivo induced overexpression of PPAR-gamma, reduced the paw swelling and inflammation, and downregulated activation and inflammation of FLS in RA. Interesting, injection of ad-Ppar-gamma into the ankle also reversed the ankle inflammation in Ppar-gamma(+/-) CIA mice. We conducted RNA-sequencing and KEGG pathway analysis, and revealed that PPAR-gamma overexpression was closely related to p53 signaling pathway in TNF-alpha-induced FLS. Co-IP study confirmed that p53 protein was bound to PPAR-gamma in RA FLS. Taken together, PPAR-gamma alleviates the inflammatory response of TNF-alpha-induced FLS by binding p53 in RA.