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

炎症 罗格列酮 过氧化物酶体增殖物激活受体 关节炎 内分泌学 内科学 类风湿性关节炎 兴奋剂 受体 医学 肿瘤坏死因子α 吡格列酮 药理学 化学 2型糖尿病 糖尿病
作者
Xiaofeng Li,Shu-qin Yin,Hao Li,Yingli Yang,Xin Chen,Biao Song,Sha Wu,Yuanyuan Wu,Hua Wang,Jun Li
出处
期刊:Acta pharmacologica Sinica [Springer Nature]
卷期号:44 (2): 454-464 被引量:9
标识
DOI:10.1038/s41401-022-00957-9
摘要

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)-γ 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-γ 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-γ+/− mice. We showed that the expression of PPAR-γ was significantly reduced, whereas that of TNF-α was markedly increased in human RA FLS. In CIA mice, knockdown of PPAR-γ expression (Ppar-γ+/−) aggravated the ankle inflammation. Similarly, T0070907 (a PPAR-γ antagonist) or si-PPAR-γ promoted the activation and inflammation of TNF-α-induced FLS in vitro. On the contrary, administration of PPAR-γ agonist pioglitazone or rosiglitazone, or injection of ad-Ppar-γ into the ankle of AIA rat in vivo induced overexpression of PPAR-γ, reduced the paw swelling and inflammation, and downregulated activation and inflammation of FLS in RA. Interesting, injection of ad-Ppar-γ into the ankle also reversed the ankle inflammation in Ppar-γ+/− CIA mice. We conducted RNA-sequencing and KEGG pathway analysis, and revealed that PPAR-γ overexpression was closely related to p53 signaling pathway in TNF-α-induced FLS. Co-IP study confirmed that p53 protein was bound to PPAR-γ in RA FLS. Taken together, PPAR-γ alleviates the inflammatory response of TNF-α-induced FLS by binding p53 in RA.
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