Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Zhou X

PROVIDER: S-EPMC7921149 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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

Zhou Xinpeng X Xie Duoli D Huang Jie J Lu Aiping A Wang Rongsheng R Jin Yehua Y Zhang Runrun R Chang Cen C Xu Lingxia L Xu Linshuai L Fan Junyu J Liang Chao C He Dongyi D

Frontiers in immunology 20210216

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 ...[more]

PMID: 33664742

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Project description:Tripterygium is a traditional Chinese medicine that has widely been used in the treatment of rheumatic disease. (5R)-5-hydroxytriptolide (LLDT-8) is an extracted compound from Tripterygium, which has been shown to have lower cytotoxicity and relatively higher immunosuppressive activity when compared to Tripterygium. However, our understanding of LLDT-8-induced epigenomic impact and overall regulatory changes in key cell types remains limited. Doing so will provide critically important mechanistic information about how LLDT-8 wields its immunosuppressive activity. The purpose of this study was to assess the effects of LLDT-8 on transcriptome including mRNAs and long non-coding RNA (lncRNAs) in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) by a custom genome-wide microarray assay. Significant differential expressed genes were validated by QPCR. Our work shows that 394 genes (281 down- and 113 up-regulated) were significantly differentially expressed in FLS responding to the treatment of LLDT-8. KEGG pathway analysis showed 20 pathways were significantly enriched and the most significantly enriched pathways were relevant to Immune reaction, including cytokine-cytokine receptor interaction (P = 4.61 × 10-13), chemokine signaling pathway (P = 1.01 × 10-5) and TNF signaling pathway (P = 2.79 × 10-4). Furthermore, we identified 618 highly negatively correlated lncRNA-mRNA pairs from the selected significantly differential lncRNA and mRNA including 27 cis-regulated and 591 trans-regulated lncRNA-mRNAs modules. KEGG and GO based function analysis to differential lncRNA also shown the enrichment of immune response. Finally, lncRNA-transcription factor (TF) and lncRNA-TF-mRNA co-expression network were constructed with high specific network characteristics, indicating LLDT-8 would influence the expression network within the whole FLS cells. The results indicated that the LLDT-8 would mainly influence the FLS cells systemically and specially in the process of immune related pathways.

Dataset Information

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

Publications

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

Similar Datasets

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