TY - JOUR
T1 - Therapeutic Effects of (5R)-5-Hydroxytriptolide on Fibroblast-Like Synoviocytes in Rheumatoid Arthritis via lncRNA WAKMAR2/miR-4478/E2F1/p53 Axis
AU - Zhou, Xinpeng
AU - Xie, Duoli
AU - Huang, Jie
AU - Lu, Aiping
AU - Wang, Rongsheng
AU - Jin, Yehua
AU - Zhang, Runrun
AU - Chang, Cen
AU - Xu, Lingxia
AU - Xu, Linshuai
AU - Fan, Junyu
AU - Liang, Chao
AU - He, Dongyi
N1 - Funding Information:
This work was supported by the Natural Science Foundation Council of China (81922081, 81774114, and 81700780), Shanghai Municipal Administrator of Traditional Chinese Medicine, Shanghai Chinese and Western Medicine Clinical Pilot Project [ZY(2018-2020)-FWTX-1010], Shanghai Municipal Administrator of Traditional Chinese Medicine, Shanghai Traditional Chinese Medicine Specialty Alliance Project [ZY(2018-2020)-FWTX-4017], National Administration of Traditional Chinese Medicine, Regional Chinese Medicine (Specialist) Diagnosis and Treatment Center Construction Project-Rheumatology, and the Croucher Foundation (Gnt#CAS14BU/CAS14201).
Publisher copyright:
Copyright © 2021 Zhou, Xie, Huang, Lu, Wang, Jin, Zhang, Chang, Xu, Xu, Fan, Liang and He.
PY - 2021/2/16
Y1 - 2021/2/16
N2 - 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.
AB - 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.
KW - (5R)-5-hydroxytriptolide
KW - fibroblast-like synoviocytes
KW - inflammation
KW - miR-4478/E2F1/p53 axis
KW - rheumatoid arthritis
KW - WAKMAR2
UR - http://www.scopus.com/inward/record.url?scp=85102011980&partnerID=8YFLogxK
U2 - 10.3389/fimmu.2021.605616
DO - 10.3389/fimmu.2021.605616
M3 - Journal article
C2 - 33664742
AN - SCOPUS:85102011980
SN - 1664-3224
VL - 12
JO - Frontiers in Immunology
JF - Frontiers in Immunology
M1 - 605616
ER -
