title: Triptolide Modulates TREM-1 Signal Pathway to Inhibit the Inflammatory Response in Rheumatoid Arthritis.
abstract: Triptolide (TP), an active component isolated from Tripterygiumwilfordii Hook F, has therapeutic potential against rheumatoid arthritis (RA). However, the underlying molecular mechanism has not been fully elucidated. The aim of this study is to investigate the mechanisms of TP acting on RA by combining bioinformatics analysis with experiment validation. The human protein targets of TP and the human genes of RA were found in the PubChem database and NCBI, respectively. These two dataset were then imported into Ingenuity Pathway Analysis (IPA) software online, and then the molecular network of TP on RA could be set up and analyzed. After that, both in vitro and in vivo experiments were done to further verify the prediction. The results indicated that the main canonical signal pathways of TP protein targets networks were mainly centered on cytokine and cellular immune signaling, and triggering receptors expressed on myeloid cells (TREM)-1 signaling was searched to be the top one shared signaling pathway and involved in the cytokine and cellular immune signaling. Further in vitro experiments indicated that TP not only remarkably lowered the levels of TREM-1 and DNAX-associated protein (DAP)12, but also significantly suppressed the activation of janus activating kinase (JAK)2 and signal transducers and activators of transcription (STAT)3. The expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 in lipopolysaccharides (LPS)-stimulated U937 cells also decreased after treatment with TP. Furthermore, TREM-1 knockdown was able to interfere with the inhibition effects of TP on these cytokines production. In vivo experiments showed that TP not only significantly inhibited the TREM-1 mRNA and DAP12 mRNA expression, and activation of JAK2 and STAT3 in ankle of rats with collagen-induced arthritis (CIA), but also remarkably decreased production of TNF-α, IL-1β and IL-6 in serum and joint. These findings demonstrated that TP could modulate the TREM1 signal pathway to inhibit the inflammatory response in RA.
authors.affiliation: Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China. zgzyfdp@126.com.
authors.forename: Danping
authors.initials: D
authors.lastname: Fan
authors.affiliation: Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China. hxj19@126.com.|Institute for Advancing Translational Medicine in Bone &amp; Joint Diseases, Hong Kong Baptist University, Hong Kong, China. hxj19@126.com.
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: He
authors.affiliation: E-Institute of Chinese Traditional Internal Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. xiaobian504@126.com.
authors.forename: Yanqin
authors.initials: Y
authors.lastname: Bian
authors.affiliation: Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China. gqq5432@163.com.|School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China. gqq5432@163.com.
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Guo
authors.affiliation: Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China. zhengkang13@126.com.
authors.forename: Kang
authors.initials: K
authors.lastname: Zheng
authors.affiliation: Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China. zhyk_87@163.com.|E-Institute of Chinese Traditional Internal Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. zhyk_87@163.com.
authors.forename: Yukun
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China. lv_cheng0816@163.com.
authors.forename: Cheng
authors.initials: C
authors.lastname: Lu
authors.affiliation: Zhengzhou Hospital of Traditional Chinese Medicine, Zhengzhou 450002, China. liubqmm@163.com.
authors.forename: Baoqin
authors.initials: B
authors.lastname: Liu
authors.affiliation: Zhengzhou Hospital of Traditional Chinese Medicine, Zhengzhou 450002, China. xuxg1115@126.com.
authors.forename: Xuegong
authors.initials: X
authors.lastname: Xu
authors.affiliation: Institute for Advancing Translational Medicine in Bone & Joint Diseases, Hong Kong Baptist University, Hong Kong, China. zhangge@hkbu.edu.hk.
authors.forename: Ge
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China. aipinglu@hkbu.edu.hk.|Institute for Advancing Translational Medicine in Bone &amp; Joint Diseases, Hong Kong Baptist University, Hong Kong, China. aipinglu@hkbu.edu.hk.|E-Institute of Chinese Traditional Internal Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. aipinglu@hkbu.edu.hk.
authors.forename: Aiping
authors.initials: A
authors.lastname: Lu
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000276:immunology; D004224:Diterpenes / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D004852:Epoxy Compounds / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology; D010616:Phenanthrenes / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D017207:Rats, Sprague-Dawley; D011971:Receptors, Immunologic / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects*; D000073871:Triggering Receptor Expressed on Myeloid Cells-1; D029757:Tripterygium / Q000737:chemistry
chemical_list: D000893:Anti-Inflammatory Agents; D000972:Antineoplastic Agents, Phytogenic; D016207:Cytokines; D004224:Diterpenes; D004852:Epoxy Compounds; D008562:Membrane Glycoproteins; D010616:Phenanthrenes; D011971:Receptors, Immunologic; C408842:TREM1 protein, human; C547511:TREM1 protein, rat; D000073871:Triggering Receptor Expressed on Myeloid Cells-1; C001899:triptolide
keywords: TREM-1 signal pathway; Triptolide; bioinformatics analysis; rheumatoid arthritis