2. Academic Validation
  3. (5R)-5-Hydroxytriptolide (LLDT-8) induces substantial epigenetic mediated immune response network changes in fibroblast-like synoviocytes from rheumatoid arthritis patients

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

  • Sci Rep. 2019 Aug 1;9(1):11155. doi: 10.1038/s41598-019-47411-1.
Shicheng Guo 1,  Jia Liu 2 3,  Ting Jiang 2 3,  Dungyang Lee 4,  Rongsheng Wang 2 3,  Xinpeng Zhou 2,  Yehua Jin 2,  Yi Shen 2 3,  Yan Wang 3,  Fengmin Bai 2 3,  Qin Ding 2 3,  Grace Wang 5,  Jianyong Zhang 6,  Xiaodong Zhou 7,  Steven J Schrodi 1 8,  Dongyi He 9 10
Affiliations

Affiliations

  • 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.
PMID: 31371761 DOI: 10.1038/s41598-019-47411-1
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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