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

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 trial...

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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
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Summary: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.
ISSN:1664-3224
1664-3224
DOI:10.3389/fimmu.2021.605616