title: Arctigenin functions as a selective agonist of estrogen receptor β to restrict mTORC1 activation and consequent Th17 differentiation.
abstract: Arctigenin was previously proven to inhibit Th17 cell differentiation and thereby attenuate colitis in mice by down-regulating the activation of mechanistic target of rapamycin complex 1 (mTORC1). The present study was performed to address its underlying mechanism in view of estrogen receptor (ER). The specific antagonist PHTPP or siRNA of ERβ largely diminished the inhibitory effect of arctigenin on the mTORC1 activation in T cell lines and primary CD4+ T cells under Th17-polarization condition, suggesting that arctigenin functioned in an ERβ-dependent manner. Moreover, arctigenin was recognized to be an agonist of ERβ, which could bind to ERβ with a moderate affinity, promote dissociation of ERβ/HSP90 complex and nuclear translocation and phosphorylation of ERβ, and increase the transcription activity. Following activation of ERβ, arctigenin inhibited the activity of mTORC1 by disruption of ERβ-raptor-mTOR complex assembly. Deficiency of ERβ markedly abolished arctigenin-mediated inhibition of Th17 cell differentiation. In colitis mice, the activation of ERβ, inhibition of mTORC1 activation and Th17 response by arctigenin were abolished by PHTPP treatment. In conclusion, ERβ might be the target protein of arctigenin responsible for inhibition of mTORC1 activation and resultant prevention of Th17 cell differentiation and colitis development.
authors.affiliation: Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Tong Jia Xiang, Nanjing, China.|Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Tong Jia Xiang, Nanjing, China.
authors.forename: Bei
authors.initials: B
authors.lastname: Tong
authors.affiliation: Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Tong Jia Xiang, Nanjing, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Tong Jia Xiang, Nanjing, China.
authors.forename: Jinque
authors.initials: J
authors.lastname: Luo
authors.affiliation: Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Tong Jia Xiang, Nanjing, China.
authors.forename: Xusheng
authors.initials: X
authors.lastname: Yuan
authors.affiliation: Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Tong Jia Xiang, Nanjing, China.
authors.forename: Zhifeng
authors.initials: Z
authors.lastname: Wei
authors.affiliation: Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Tong Jia Xiang, Nanjing, China.
authors.forename: Mengfan
authors.initials: M
authors.lastname: Yue
authors.affiliation: Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Tong Jia Xiang, Nanjing, China.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Tong Jia Xiang, Nanjing, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Dai
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D003092:Colitis / Q000139:chemically induced / Q000201:enzymology / Q000378:metabolism / Q000517:prevention & control*; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D065171:Estrogen Receptor Antagonists / Q000494:pharmacology; D047629:Estrogen Receptor beta / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D005260:Female; D005663:Furans / Q000494:pharmacology*; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D017705:Lignans / Q000494:pharmacology*; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D010052:Ovariectomy; D010766:Phosphorylation; D000076223:Regulatory-Associated Protein of mTOR / Q000378:metabolism; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D058504:Th17 Cells / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: C000600034:ESR2 protein, human; D065171:Estrogen Receptor Antagonists; D047629:Estrogen Receptor beta; D005663:Furans; D018841:HSP90 Heat-Shock Proteins; D017705:Lignans; D000076223:Regulatory-Associated Protein of mTOR; C540162:Rptor protein, mouse; D020845:Selective Estrogen Receptor Modulators; D016264:Dextran Sulfate; D000076222:Mechanistic Target of Rapamycin Complex 1; C071942:arctigenin
keywords: Immune response; Immunity; Immunology and Microbiology Section; Th17 cell differentiation; arctigenin; colitis; estrogen receptor β; mTORC1 activation