Therapeutic Effects of (5R)-5-Hydroxytriptolide on Fibroblast-Like Synoviocytes in Rheumatoid Arthritis via lncRNA WAKMAR2/miR-4478/E2F1/p53 Axis

• Published in: Frontiers in immunology 2021-02, Vol.12, p.605616-605616
• Main Authors: Zhou, Xinpeng, Xie, Duoli, Huang, Jie, Lu, Aiping, Wang, Rongsheng, Jin, Yehua, Zhang, Runrun, Chang, Cen, Xu, Lingxia, Xu, Linshuai, Fan, Junyu, Liang, Chao, He, Dongyi
• Format: Article
• Language: English
• Subjects: (5R)-5-hydroxytriptolide; fibroblast-like synoviocytes; Immunology; inflammation; miR-4478/E2F1/p53 axis; rheumatoid arthritis; WAKMAR2
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2021.605616

Rheumatoid arthritis (RA) is an autoimmune disease. Fibroblast-like synoviocytes (FLS) serve a major role in synovial hyperplasia and inflammation in RA. (5R)-5-hydroxytriptolide (LLDT-8), a novel triptolide derivative, shows promising therapeutic effects for RA and is now in phase II clinical trials in China. However, the underlying mechanism of LLDT-8 is still not fully understood. Here, we found that LLDT-8 inhibited proliferation and invasion of RA FLS, as well as the production of cytokines. Microarray data demonstrated that LLDT-8 upregulated the expression of long non-coding RNA (lncRNA) WAKMAR2, which was negatively associated with proliferation and invasion of RA FLS, as well as the production of pro-inflammatory cytokines. Knockdown of WAKMAR2 abolished the inhibitory effects of LLDT-8 on RA FLS. Mechanistically, WAKMAR2 sponged miR-4478, which targeted E2F1 and downstreamed p53 signaling. Rescue experiments indicated that the inhibitory effects of LLDT-8 on RA FLS were dependent on WAKMAR2/miR-4478/E2F1/p53 axis.