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.