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

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

doi:10.18632/oncotarget.13338

Xin Wu, Zhifeng Wei + Show 7 more

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https://doi.org/10.18632/oncotarget.13338

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Journal: Oncotarget	Publication Date: Nov 14, 2016
Citations: 23	License type: cc-by

Affiliation: Southwest Hospital, China Pharmaceutical University

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.

Highlights

Ulcerative colitis (UC) is a chronic non-specific inflammatory disease affecting the colonic mucosa, and Th17 cells have been recognized to play a crucial role in its onset and progression [1]
The findings indicated that ERβ, but not ERα or GPER, mediated the inhibition of arctigenin against mechanistic target of rapamycin complex 1 (mTORC1) pathway in T cells
Mice treated with arctigenin or E2 in combination with PHTPP displayed higher disease activity index (DAI) scores, reduced colon length (Figure 6F and 6G), increased expressions of pro-inflammatory cytokines TNF-α and IL-6 (Figure 6H) and severe inflammatory damage (Figure 6I and 6J), as compared to those treated with arctigenin or E2 alone. These results indicated that the activation of ERβ induced by arctigenin played a crucial role in inhibition of mTORC1 activation, generation of Th17 cells, and eventual attenuation of pathological changes of colitis, and ERβ agonist might be a promising strategy for prevention of colitis

Summary

Introduction

Ulcerative colitis (UC) is a chronic non-specific inflammatory disease affecting the colonic mucosa, and Th17 cells have been recognized to play a crucial role in its onset and progression [1]. Its predominant form E2, could inhibit mTOR activation in osteoblasts [7], and phytoestrogens calycosin and liquiritigenin inhibited the activation of mTOR pathway in breast cancer cells and glioma cells, respectively [8, 9]. These findings suggest a possibility that arctigenin acts as a ligand of ER subtype to inhibit the activation of mTORC1

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