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Sci Rep. 2019 Aug 1;9(1):11155. doi: 10.1038/s41598-019-47411-1.

(5R)-5-Hydroxytriptolide (LLDT-8) induces substantial epigenetic mediated immune response network changes in fibroblast-like synoviocytes from rheumatoid arthritis patients.

Guo S1, Liu J2,3, Jiang T2,3, Lee D4, Wang R2,3, Zhou X2, Jin Y2, Shen Y2,3, Wang Y3, Bai F2,3, Ding Q2,3, Wang G5, Zhang J6, Zhou X7, Schrodi SJ1,8, He D9,10.

Author information

1
Center for Precision Medicine Research, Marshfield Clinic Research Institute, Marshfield, WI, United States, 54449.
2
Department of Rheumatology, Shanghai Guanghua Hospital of Integrated Traditional and Western Medicine, Shanghai, 200052, China.
3
Arthritis Institute of integrated Traditional and Western medicine, Shanghai Chinese Medicine Research Institute, Shanghai, 200052, China.
4
Division of Biostatistics, University of Texas School of Public Health, Houston, TX, USA.
5
Washington University, St. Louis, Missouri, 63130, USA.
6
Shenzhen Traditional Chinese Medicine Hospital and The fourth Clinical Medical College of Guangzhou University of Chinese Medicine. Fuhua Road, Shenzhen, Guangzhou, 518033, China.
7
University of Texas Medical School at Houston, 6431 Fannin, MSB5.270, Houston, TX, 77030, USA.
8
Computation and Informatics in Biology and Medicine, University of Wisconsin-Madison, Madison, WI, 53706, USA.
9
Department of Rheumatology, Shanghai Guanghua Hospital of Integrated Traditional and Western Medicine, Shanghai, 200052, China. dongyihe@medmail.com.cn.
10
Arthritis Institute of integrated Traditional and Western medicine, Shanghai Chinese Medicine Research Institute, Shanghai, 200052, China. dongyihe@medmail.com.cn.

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 × 10-13), 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.

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