Oncotarget

Research Papers: Immunology:

Arctigenin functions as a selective agonist of estrogen receptor β to restrict mTORC1 activation and consequent Th17 differentiation

Xin Wu, Bei Tong, Yan Yang, Jinque Luo, Xusheng Yuan, Zhifeng Wei, Mengfan Yue, Yufeng Xia and Yue Dai _

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Oncotarget. 2016; 7:83893-83906. https://doi.org/10.18632/oncotarget.13338

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Abstract

Xin Wu1,2, Bei Tong1, Yan Yang1, Jinque Luo1, Xusheng Yuan1, Zhifeng Wei1, Mengfan Yue1, Yufeng Xia1 and Yue Dai1

1 Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Tong Jia Xiang, Nanjing, China

2 Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China

Correspondence to:

Yue Dai, email:

Yufeng Xia, email:

Keywords: arctigenin, estrogen receptor β, mTORC1 activation, Th17 cell differentiation, colitis, Immunology and Microbiology Section, Immune response, Immunity

Received: August 26, 2016 Accepted: November 08, 2016 Published: November 14, 2016

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.


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