Premium
Therapeutic Effect of Oridonin Against Inflammatory Bowel Disease Involves Inhibition of Intestinal Fibrosis via NF‐κB Pathway
Author(s) -
Wang Xiaofu,
Cummins Claire,
Gu Yanping,
Song Juquan,
Zhou Jia,
Radhakrishnan Ravi
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/fasebj.2020.34.s1.06182
Subject(s) - fibronectin , inflammatory bowel disease , epithelial–mesenchymal transition , chemistry , tumor necrosis factor alpha , cancer research , myofibroblast , secretion , inflammation , nf κb , iκbα , western blot , cytokine , fibrosis , extracellular matrix , immunology , medicine , downregulation and upregulation , biochemistry , disease , gene
Intestinal fibrosis and stricture formation are frequent complications of inflammatory bowel disease (IBD). In response to inflammatory stimuli, intestinal epithelial cells may undergo epithelial‐mesenchymal transition (EMT). EMT is a process by which epithelial cells acquire a mesenchymal‐like phenotype, resulting in intestinal fibrosis. Oridonin, a bioactive diterpenoid isolated from Rabdosia rubescens, was reported to have therapeutic effects for IBD. However, the cellular mechanism remains unclear. We hypothesize that oridonin attenuates inflammation‐related EMT and fibrogenesis in intestinal epithelial cells. Methods IEC‐6 and IEC‐18 cells exposed to TNFα were pre‐treated with or without oridonin. Cellular proteins were analyzed with Western blot or immunofluorescence assay. Cytokine secretion was determined with ELISA. Results Oridonin treatment suppressed TNFα‐induced NF‐κB activation evidenced by blocking TNFα‐induced NF‐κB p65 nuclear translocation and DNA binding activity. TNFα‐induced phosphorylation of IKKα/β and IκBα as well as total IκBα degradation were prevented by oridonin. TNFα‐stimulated secretion of pro‐inflammatory cytokine IL‐6 was inhibited by oridonin. Oridonin moderately up‐regulates endogenous E‐cadherin and down‐regulates Snail. The expression of extracellular matrix proteins fibronectin and laminin were increased by TNFα and suppressed by pre‐treatment with oridonin. For the first time, we demonstrated that TNFα dose‐dependently up‐regulated α‐smooth muscle actin (α‐SMA), a myofibroblast marker, in IEC‐6 cells. These results indicate that IEC‐6 cells underwent transition into mesenchymal cells after TNFα stimulation. Notably, oridonin inhibited TNFα‐stimulated α‐SMA, but not TGFβ1‐stimulated EMT‐related proteins. Conclusion The protective effects of oridonin in intestinal epithelial cells may occur through suppression of the TNFα‐induced NF‐κB pathway and EMT‐related fibrogenesis.