title: SH479, a Betulinic Acid Derivative, Ameliorates Experimental Autoimmune Encephalomyelitis by Regulating the T Helper 17/Regulatory T Cell Balance.
abstract: CD4+T helper cells, especially T helper 17 (TH17) cells, combined with immune regulatory network dysfunction, play key roles in autoimmune diseases including multiple sclerosis (MS). Betulinic acid (BA), a natural pentacyclic triterpenoid, has been reported to be involved in anti-inflammation, in particular having an inhibitory effect on proinflammatory cytokine interleukin 17 (IL-17) and interferon-γ(IFN-γ) production. In this study, we screened BA derivatives and found a BA derivative, SH479, that had a greater inhibitory effect on TH17 differentiation. Our further analysis showed that SH479 had a greater inhibitory effect on TH17 and TH1, and a more stimulatory effect on regulatory T (Treg) cells. To evaluate the effects of SH479 on autoimmune diseases in vivo, we employed the extensively used MS mouse model experimental autoimmune encephalomyelitis (EAE). Our results showed that SH479 ameliorated clinical and histologic signs of EAE in both prevention and therapeutic protocols by regulating the TH17/Treg balance. SH479 dose-dependently reduced splenic lymphocyte proinflammatory factors and increased anti-inflammatory factors. Moreover, SH479 specifically inhibited splenic lymphocyte viability from EAE mice but not normal splenic lymphocyte viability. At the molecular level, SH479 inhibited TH17 differentiation by regulating signal transducer and activator of transcription-3 (STAT3) phosphorylation, DNA binding activity, and recruitment to theIl-17apromoter in CD4+T cells. Furthermore, SH479 promoted the STAT5 signaling pathway and inhibited the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway. Together, our data demonstrated that SH479 ameliorated EAE by regulating the TH17/Treg balance through inhibiting the STAT3 and NF-κB pathways while activating the STAT5 pathway, suggesting that SH479 is a potential novel drug candidate for autoimmune diseases including MS.
authors.affiliation: Shanghai Fengxian District Central Hospital, Shanghai, People's Republic of China (J.Li); Shanghai Fengxian District Central Hospital and East China Normal University Joint Center for Translational Medicine, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, People's Republic of China (J.J., Y.B., Z.L., R.X., B.T., X.M., B.D., M.L., H.C., J.Luo); Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, People's Republic of China (W.-W.Q., F.Y., J.T.); Laboratory of Receptor-Based Bio-medicine, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, People's Republic of China (C.D.); Institute of Biosciences and Technology, Department of Molecular and Cellular Medicine, Texas A&M University Health Science Center, Houston, Texas (S.S., M.L.).
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Shanghai Fengxian District Central Hospital, Shanghai, People's Republic of China (J.Li); Shanghai Fengxian District Central Hospital and East China Normal University Joint Center for Translational Medicine, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, People's Republic of China (J.J., Y.B., Z.L., R.X., B.T., X.M., B.D., M.L., H.C., J.Luo); Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, People's Republic of China (W.-W.Q., F.Y., J.T.); Laboratory of Receptor-Based Bio-medicine, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, People's Republic of China (C.D.); Institute of Biosciences and Technology, Department of Molecular and Cellular Medicine, Texas A&M University Health Science Center, Houston, Texas (S.S., M.L.).
authors.forename: Ji
authors.initials: J
authors.lastname: Jing
authors.affiliation: Shanghai Fengxian District Central Hospital, Shanghai, People's Republic of China (J.Li); Shanghai Fengxian District Central Hospital and East China Normal University Joint Center for Translational Medicine, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, People's Republic of China (J.J., Y.B., Z.L., R.X., B.T., X.M., B.D., M.L., H.C., J.Luo); Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, People's Republic of China (W.-W.Q., F.Y., J.T.); Laboratory of Receptor-Based Bio-medicine, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, People's Republic of China (C.D.); Institute of Biosciences and Technology, Department of Molecular and Cellular Medicine, Texas A&M University Health Science Center, Houston, Texas (S.S., M.L.).
authors.forename: Yang
authors.initials: Y
authors.lastname: Bai
authors.affiliation: Shanghai Fengxian District Central Hospital, Shanghai, People's Republic of China (J.Li); Shanghai Fengxian District Central Hospital and East China Normal University Joint Center for Translational Medicine, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, People's Republic of China (J.J., Y.B., Z.L., R.X., B.T., X.M., B.D., M.L., H.C., J.Luo); Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, People's Republic of China (W.-W.Q., F.Y., J.T.); Laboratory of Receptor-Based Bio-medicine, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, People's Republic of China (C.D.); Institute of Biosciences and Technology, Department of Molecular and Cellular Medicine, Texas A&M University Health Science Center, Houston, Texas (S.S., M.L.).
authors.forename: Zhen
authors.initials: Z
authors.lastname: Li
authors.affiliation: Shanghai Fengxian District Central Hospital, Shanghai, People's Republic of China (J.Li); Shanghai Fengxian District Central Hospital and East China Normal University Joint Center for Translational Medicine, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, People's Republic of China (J.J., Y.B., Z.L., R.X., B.T., X.M., B.D., M.L., H.C., J.Luo); Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, People's Republic of China (W.-W.Q., F.Y., J.T.); Laboratory of Receptor-Based Bio-medicine, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, People's Republic of China (C.D.); Institute of Biosciences and Technology, Department of Molecular and Cellular Medicine, Texas A&M University Health Science Center, Houston, Texas (S.S., M.L.).
authors.forename: Roumei
authors.initials: R
authors.lastname: Xing
authors.affiliation: Shanghai Fengxian District Central Hospital, Shanghai, People's Republic of China (J.Li); Shanghai Fengxian District Central Hospital and East China Normal University Joint Center for Translational Medicine, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, People's Republic of China (J.J., Y.B., Z.L., R.X., B.T., X.M., B.D., M.L., H.C., J.Luo); Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, People's Republic of China (W.-W.Q., F.Y., J.T.); Laboratory of Receptor-Based Bio-medicine, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, People's Republic of China (C.D.); Institute of Biosciences and Technology, Department of Molecular and Cellular Medicine, Texas A&M University Health Science Center, Houston, Texas (S.S., M.L.).
authors.forename: Binhe
authors.initials: B
authors.lastname: Tan
authors.affiliation: Shanghai Fengxian District Central Hospital, Shanghai, People's Republic of China (J.Li); Shanghai Fengxian District Central Hospital and East China Normal University Joint Center for Translational Medicine, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, People's Republic of China (J.J., Y.B., Z.L., R.X., B.T., X.M., B.D., M.L., H.C., J.Luo); Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, People's Republic of China (W.-W.Q., F.Y., J.T.); Laboratory of Receptor-Based Bio-medicine, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, People's Republic of China (C.D.); Institute of Biosciences and Technology, Department of Molecular and Cellular Medicine, Texas A&M University Health Science Center, Houston, Texas (S.S., M.L.).
authors.forename: Xueyun
authors.initials: X
authors.lastname: Ma
authors.affiliation: Shanghai Fengxian District Central Hospital, Shanghai, People's Republic of China (J.Li); Shanghai Fengxian District Central Hospital and East China Normal University Joint Center for Translational Medicine, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, People's Republic of China (J.J., Y.B., Z.L., R.X., B.T., X.M., B.D., M.L., H.C., J.Luo); Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, People's Republic of China (W.-W.Q., F.Y., J.T.); Laboratory of Receptor-Based Bio-medicine, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, People's Republic of China (C.D.); Institute of Biosciences and Technology, Department of Molecular and Cellular Medicine, Texas A&M University Health Science Center, Houston, Texas (S.S., M.L.).
authors.forename: Wen-Wei
authors.initials: WW
authors.lastname: Qiu
authors.affiliation: Shanghai Fengxian District Central Hospital, Shanghai, People's Republic of China (J.Li); Shanghai Fengxian District Central Hospital and East China Normal University Joint Center for Translational Medicine, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, People's Republic of China (J.J., Y.B., Z.L., R.X., B.T., X.M., B.D., M.L., H.C., J.Luo); Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, People's Republic of China (W.-W.Q., F.Y., J.T.); Laboratory of Receptor-Based Bio-medicine, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, People's Republic of China (C.D.); Institute of Biosciences and Technology, Department of Molecular and Cellular Medicine, Texas A&M University Health Science Center, Houston, Texas (S.S., M.L.).
authors.forename: Changsheng
authors.initials: C
authors.lastname: Du
authors.affiliation: Shanghai Fengxian District Central Hospital, Shanghai, People's Republic of China (J.Li); Shanghai Fengxian District Central Hospital and East China Normal University Joint Center for Translational Medicine, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, People's Republic of China (J.J., Y.B., Z.L., R.X., B.T., X.M., B.D., M.L., H.C., J.Luo); Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, People's Republic of China (W.-W.Q., F.Y., J.T.); Laboratory of Receptor-Based Bio-medicine, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, People's Republic of China (C.D.); Institute of Biosciences and Technology, Department of Molecular and Cellular Medicine, Texas A&M University Health Science Center, Houston, Texas (S.S., M.L.).
authors.forename: Bing
authors.initials: B
authors.lastname: Du
authors.affiliation: Shanghai Fengxian District Central Hospital, Shanghai, People's Republic of China (J.Li); Shanghai Fengxian District Central Hospital and East China Normal University Joint Center for Translational Medicine, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, People's Republic of China (J.J., Y.B., Z.L., R.X., B.T., X.M., B.D., M.L., H.C., J.Luo); Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, People's Republic of China (W.-W.Q., F.Y., J.T.); Laboratory of Receptor-Based Bio-medicine, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, People's Republic of China (C.D.); Institute of Biosciences and Technology, Department of Molecular and Cellular Medicine, Texas A&M University Health Science Center, Houston, Texas (S.S., M.L.).
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.affiliation: Shanghai Fengxian District Central Hospital, Shanghai, People's Republic of China (J.Li); Shanghai Fengxian District Central Hospital and East China Normal University Joint Center for Translational Medicine, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, People's Republic of China (J.J., Y.B., Z.L., R.X., B.T., X.M., B.D., M.L., H.C., J.Luo); Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, People's Republic of China (W.-W.Q., F.Y., J.T.); Laboratory of Receptor-Based Bio-medicine, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, People's Republic of China (C.D.); Institute of Biosciences and Technology, Department of Molecular and Cellular Medicine, Texas A&M University Health Science Center, Houston, Texas (S.S., M.L.).
authors.forename: Jie
authors.initials: J
authors.lastname: Tang
authors.affiliation: Shanghai Fengxian District Central Hospital, Shanghai, People's Republic of China (J.Li); Shanghai Fengxian District Central Hospital and East China Normal University Joint Center for Translational Medicine, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, People's Republic of China (J.J., Y.B., Z.L., R.X., B.T., X.M., B.D., M.L., H.C., J.Luo); Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, People's Republic of China (W.-W.Q., F.Y., J.T.); Laboratory of Receptor-Based Bio-medicine, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, People's Republic of China (C.D.); Institute of Biosciences and Technology, Department of Molecular and Cellular Medicine, Texas A&M University Health Science Center, Houston, Texas (S.S., M.L.).
authors.forename: Stefan
authors.initials: S
authors.lastname: Siwko
authors.affiliation: Shanghai Fengxian District Central Hospital, Shanghai, People's Republic of China (J.Li); Shanghai Fengxian District Central Hospital and East China Normal University Joint Center for Translational Medicine, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, People's Republic of China (J.J., Y.B., Z.L., R.X., B.T., X.M., B.D., M.L., H.C., J.Luo); Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, People's Republic of China (W.-W.Q., F.Y., J.T.); Laboratory of Receptor-Based Bio-medicine, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, People's Republic of China (C.D.); Institute of Biosciences and Technology, Department of Molecular and Cellular Medicine, Texas A&M University Health Science Center, Houston, Texas (S.S., M.L.) jluo@bio.ecnu.edu.cn myliu@bio.ecnu.edu.cn hqchen@bio.ecnu.edu.cn.
authors.forename: Mingyao
authors.initials: M
authors.lastname: Liu
authors.affiliation: Shanghai Fengxian District Central Hospital, Shanghai, People's Republic of China (J.Li); Shanghai Fengxian District Central Hospital and East China Normal University Joint Center for Translational Medicine, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, People's Republic of China (J.J., Y.B., Z.L., R.X., B.T., X.M., B.D., M.L., H.C., J.Luo); Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, People's Republic of China (W.-W.Q., F.Y., J.T.); Laboratory of Receptor-Based Bio-medicine, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, People's Republic of China (C.D.); Institute of Biosciences and Technology, Department of Molecular and Cellular Medicine, Texas A&M University Health Science Center, Houston, Texas (S.S., M.L.) jluo@bio.ecnu.edu.cn myliu@bio.ecnu.edu.cn hqchen@bio.ecnu.edu.cn.
authors.forename: Huaqing
authors.initials: H
authors.lastname: Chen
authors.affiliation: Shanghai Fengxian District Central Hospital, Shanghai, People's Republic of China (J.Li); Shanghai Fengxian District Central Hospital and East China Normal University Joint Center for Translational Medicine, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, People's Republic of China (J.J., Y.B., Z.L., R.X., B.T., X.M., B.D., M.L., H.C., J.Luo); Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, People's Republic of China (W.-W.Q., F.Y., J.T.); Laboratory of Receptor-Based Bio-medicine, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, People's Republic of China (C.D.); Institute of Biosciences and Technology, Department of Molecular and Cellular Medicine, Texas A&M University Health Science Center, Houston, Texas (S.S., M.L.) jluo@bio.ecnu.edu.cn myliu@bio.ecnu.edu.cn hqchen@bio.ecnu.edu.cn.
authors.forename: Jian
authors.initials: J
authors.lastname: Luo
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D006801:Humans; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D053978:Pentacyclic Triterpenes; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013154:Spleen / Q000187:drug effects / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology*; D014315:Triterpenes / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D000094062:Betulinic Acid
chemical_list: D000893:Anti-Inflammatory Agents; D016328:NF-kappa B; D053978:Pentacyclic Triterpenes; C000618011:SH479 compound; D050791:STAT Transcription Factors; D014315:Triterpenes; D000094062:Betulinic Acid