(5R)-5-Hydroxytriptolide (LLDT-8) Induces Substantial Epigenetic Mediated Immune Response Network Changes in Fibroblast-like Synoviocytes from Rheumatoid Arthritis Patients

Overview

Journal Sci Rep

Specialty Science

Date 2019 Aug 3

PMID 31371761

Citations 14

Authors

Shicheng Guo

Jia Liu

Ting Jiang

Dungyang Lee

Rongsheng Wang

Xinpeng Zhou

Yehua Jin

Yi Shen

Yan Wang

Fengmin Bai

Qin Ding

Grace Wang

Jianyong Zhang

Xiaodong Zhou

Steven J Schrodi

Dongyi He

Affiliations

Soon will be listed here.

Abstract

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), chemokine signaling pathway (P = 1.01 × 10) and TNF signaling pathway (P = 2.79 × 10). 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.

Citing Articles

A comprehensive review of hook. f. in the treatment of rheumatic and autoimmune diseases: Bioactive compounds, mechanisms of action, and future directions.

Shan Y, Zhao J, Wei K, Jiang P, Xu L, Chang C Front Pharmacol. 2023; 14:1282610.

PMID: 38027004 PMC: 10646552. DOI: 10.3389/fphar.2023.1282610.

The therapeutic potential of triptolide and celastrol in neurological diseases.

Cui Y, Jiang X, Feng J Front Pharmacol. 2022; 13:1024955.

PMID: 36339550 PMC: 9626530. DOI: 10.3389/fphar.2022.1024955.

An intersectional analysis of LncRNAs and mRNAs reveals the potential therapeutic targets of Bi Zhong Xiao Decoction in collagen-induced arthritis rats.

He C, Wang Y, Wen Y, Li T, Hu E, Zeng S Chin Med. 2022; 17(1):110.

PMID: 36109779 PMC: 9479270. DOI: 10.1186/s13020-022-00670-z.

MicroRNA-Mediated Epigenetic Regulation of Rheumatoid Arthritis Susceptibility and Pathogenesis.

Chang C, Xu L, Zhang R, Jin Y, Jiang P, Wei K Front Immunol. 2022; 13:838884.

PMID: 35401568 PMC: 8987113. DOI: 10.3389/fimmu.2022.838884.

Epigenetic Regulation in the Pathogenesis of Rheumatoid Arthritis.

Yang C, Li D, Teng D, Zhou Y, Zhang L, Zhong Z Front Immunol. 2022; 13:859400.

PMID: 35401513 PMC: 8989414. DOI: 10.3389/fimmu.2022.859400.

References

Wang H, Jiang Q, Feng X, Zhang H, Ge L, Luo C . Tripterygium wilfordii Hook F versus conventional synthetic disease-modifying anti-rheumatic drugs as monotherapy for rheumatoid arthritis: a systematic review and network meta-analysis. BMC Complement Altern Med. 2016; 16:215. PMC: 4944439. DOI: 10.1186/s12906-016-1194-x. View

Chou C . Alternative therapies: what role do they have in the management of lupus?. Lupus. 2010; 19(12):1425-9. DOI: 10.1177/0961203310379872. View

Ong C, Corces V . Modulation of CTCF insulator function by transcription of a noncoding RNA. Dev Cell. 2008; 15(4):489-90. PMC: 3040117. DOI: 10.1016/j.devcel.2008.09.013. View

Messemaker T, Frank-Bertoncelj M, Marques R, Adriaans A, Bakker A, Daha N . A novel long non-coding RNA in the rheumatoid arthritis risk locus TRAF1-C5 influences C5 mRNA levels. Genes Immun. 2015; 17(2):85-92. DOI: 10.1038/gene.2015.54. View

Guttman M, Rinn J . Modular regulatory principles of large non-coding RNAs. Nature. 2012; 482(7385):339-46. PMC: 4197003. DOI: 10.1038/nature10887. View

Zhou R, Zhang F, He P, Zhou W, Wu Q, Xu J . (5R)-5-hydroxytriptolide (LLDT-8), a novel triptolide analog mediates immunosuppressive effects in vitro and in vivo. Int Immunopharmacol. 2005; 5(13-14):1895-903. DOI: 10.1016/j.intimp.2005.06.009. View

Shannon P, Markiel A, Ozier O, Baliga N, Wang J, Ramage D . Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 2003; 13(11):2498-504. PMC: 403769. DOI: 10.1101/gr.1239303. View

Tang W, Yang Y, Zhang F, Li Y, Zhou R, Wang J . Prevention of graft-versus-host disease by a novel immunosuppressant, (5R)-5-hydroxytriptolide (LLDT-8), through expansion of regulatory T cells. Int Immunopharmacol. 2005; 5(13-14):1904-13. DOI: 10.1016/j.intimp.2005.06.010. View

Ren Y, Zhou R, Tang W, Wang W, Li Y, Yang Y . (5R)-5-hydroxytriptolide (LLDT-8) protects against bleomycin-induced lung fibrosis in mice. Acta Pharmacol Sin. 2007; 28(4):518-25. DOI: 10.1111/j.1745-7254.2007.00524.x. View

10.

Bent S, Ko R . Commonly used herbal medicines in the United States: a review. Am J Med. 2004; 116(7):478-85. DOI: 10.1016/j.amjmed.2003.10.036. View

11.

Aletaha D, Neogi T, Silman A, Funovits J, Felson D, Bingham 3rd C . 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis. 2010; 69(9):1580-8. DOI: 10.1136/ard.2010.138461. View

12.

Khalil A, Guttman M, Huarte M, Garber M, Raj A, Rivea Morales D . Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression. Proc Natl Acad Sci U S A. 2009; 106(28):11667-72. PMC: 2704857. DOI: 10.1073/pnas.0904715106. View

13.

Cui Y, Zheng Y, Tan G, Zhang D, Wang J, Wang X . (5R)-5-hydroxytriptolide inhibits the inflammatory cascade reaction in astrocytes. Neural Regen Res. 2019; 14(5):913-920. PMC: 6375032. DOI: 10.4103/1673-5374.249240. View

14.

Wu G, Pan H, Leng R, Wang D, Li X, Li X . Emerging role of long noncoding RNAs in autoimmune diseases. Autoimmun Rev. 2015; 14(9):798-805. DOI: 10.1016/j.autrev.2015.05.004. View

15.

Zhai W, Li X, Wu S, Zhang Y, Pang H, Chen W . Microarray expression profile of lncRNAs and the upregulated ASLNC04080 lncRNA in human endometrial carcinoma. Int J Oncol. 2015; 46(5):2125-37. DOI: 10.3892/ijo.2015.2897. View

16.

Li J, Chen Z, Tian L, Zhou C, He M, Gao Y . LncRNA profile study reveals a three-lncRNA signature associated with the survival of patients with oesophageal squamous cell carcinoma. Gut. 2014; 63(11):1700-10. PMC: 4215280. DOI: 10.1136/gutjnl-2013-305806. View

17.

Shi H, Cao N, Pu Y, Xie L, Zheng L, Yu C . Long non-coding RNA expression profile in minor salivary gland of primary Sjögren's syndrome. Arthritis Res Ther. 2016; 18(1):109. PMC: 4869341. DOI: 10.1186/s13075-016-1005-2. View

18.

Zhou J, Yang L, Zhong T, Mueller M, Men Y, Zhang N . H19 lncRNA alters DNA methylation genome wide by regulating S-adenosylhomocysteine hydrolase. Nat Commun. 2015; 6:10221. PMC: 4703905. DOI: 10.1038/ncomms10221. View

19.

Firestein G . Evolving concepts of rheumatoid arthritis. Nature. 2003; 423(6937):356-61. DOI: 10.1038/nature01661. View

20.

Gu W, Gao T, Sun Y, Zheng X, Wang J, Ma J . LncRNA expression profile reveals the potential role of lncRNAs in gastric carcinogenesis. Cancer Biomark. 2015; 15(3):249-58. DOI: 10.3233/CBM-150460. View