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Pharmacological activation of ERβ by arctigenin maintains the integrity of intestinal epithelial barrier in inflammatory bowel diseases
Author(s) -
Tao Yu,
Yue Mengfan,
Lv Changjun,
Yun Xinming,
Qiao Simiao,
Fang Yulai,
Wei Zhifeng,
Xia Yufeng,
Dai Yue
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201901638rr
Subject(s) - barrier function , tight junction , chemistry , myosin light chain kinase , colitis , caco 2 , intestinal permeability , inflammatory bowel disease , microbiology and biotechnology , pathogenesis , immunology , myosin , biology , biochemistry , medicine , in vitro , disease
Intestinal epithelial barrier dysfunction is deeply involved in the pathogenesis of inflammatory bowel diseases (IBD). Arctigenin, the main active constituent in Fructus Arctii (a traditional Chinese medicine), has previously been found to attenuate colitis induced by dextran sulfate sodium (DSS) in mice. The present study investigated whether and how arctigenin protects against the disruption of the intestinal epithelial barrier in IBD. Arctigenin maintained the intestinal epithelial barrier function of mice with DSS‐ and TNBS‐induced colitis. In Caco‐2 and HT‐29 cells, arctigenin lowered the monolayer permeability, increased TEER, reversed the abnormal expression of tight junction proteins, and restored the altered localization of F‐actin induced by TNF‐α and IL‐1β. The specific antagonist PHTPP or shRNA of ERβ largely weakened the protective effect of arctigenin on the epithelial barrier function of Caco‐2 and HT‐29 cells. Molecular docking demonstrated that arctigenin had high affinity for ERβ mainly through hydrogen bonds as well as hydrophobic effects, and the protective effect of arctigenin on the intestinal barrier function was largely diminished in ERβ‐mutated (ARG346 and/or GLU305) Caco‐2 cells. Moreover, arctigenin‐blocked TNF‐α induced increase of the monolayer permeability in Caco‐2 and HT‐29 cells and the activation of myosin light chain kinase (MLCK)/myosin light chain (MLC) pathway in an ERβ‐dependent manner. ERβ deletion in colons of mice with DSS‐induced colitis resulted in a significant attenuation of the protective effect of arctigenin on the barrier integrity and colon inflammation. Arctigenin maintained the integrity of the intestinal epithelial barrier under IBD by upregulating the expression of tight junction proteins through the ERβ‐MLCK/MLC pathway.