title: Embelin suppresses dendritic cell functions and limits autoimmune encephalomyelitis through the TGF-β/β-catenin and STAT3 signaling pathways.
abstract: Embelin (2,5-dihydroxy-3-undecyl-1,4-benzoquinone, EB) has been shown to inhibit the X-linked inhibitor of apoptosis protein and various inflammatory pathways. Although different molecular mechanisms have been described for the potent antitumor activities of EB, its potential effect on inflammatory and immune-mediated diseases such as multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE) remains unclear. In this study, we demonstrated that EB suppressed human CD14(+) monocyte-derived dendritic cell (DC) differentiation, maturation, and endocytosis and further inhibited the stimulatory function of mature DCs on allogeneic T cell proliferation in vitro. In addition, EB blocked the DC-derived expression of the Th1 cell-polarizing cytokines interferon-γ and interleukin (IL)-12 and the Th17 cell-polarizing cytokines IL-6 and IL-23. In vivo administration of EB led to a reduction in the EAE clinical score, in central nervous system inflammation, and in demyelination. Furthermore, EB also suppressed inflammatory Th1 and Th17 cells in EAE, at least partially, through the promotion of transforming growth factor-beta and β-catenin expression and inhibition of signal transducer and activator of transcription 3 signaling pathways in DCs. These data suggest that EB has potent anti-inflammatory and immunosuppressive properties and is a potential therapeutic drug for MS and other autoimmune inflammatory diseases.
authors.affiliation: Laboratory of Immunology and Inflammation, Research Center of Basic Medical Science, Tianjin Medical University, Tianjin, 300070, China.
authors.forename: Zhenyi
authors.initials: Z
authors.lastname: Xue
authors.forename: Zhenzhen
authors.initials: Z
authors.lastname: Ge
authors.forename: Kai
authors.initials: K
authors.lastname: Zhang
authors.forename: Rui
authors.initials: R
authors.lastname: Sun
authors.forename: Juhong
authors.initials: J
authors.lastname: Yang
authors.forename: Rong
authors.initials: R
authors.lastname: Han
authors.forename: Meiyu
authors.initials: M
authors.lastname: Peng
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Wen
authors.initials: W
authors.lastname: Li
authors.forename: Da
authors.initials: D
authors.lastname: Zhang
authors.forename: Junwei
authors.initials: J
authors.lastname: Hao
authors.forename: Yurong
authors.initials: Y
authors.lastname: Da
authors.forename: Zhi
authors.initials: Z
authors.lastname: Yao
authors.forename: Rongxin
authors.initials: R
authors.lastname: Zhang
mesh_terms: D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology / Q000627:therapeutic use*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000378:metabolism*; D005260:Female; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000096:biosynthesis*; D051176:beta Catenin / Q000096:biosynthesis*
chemical_list: D016227:Benzoquinones; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D016212:Transforming Growth Factor beta; D051176:beta Catenin; C010945:embelin