Activation of PXR by alantolactone ameliorates DSS-induced experimental colitis via suppressing NF-κB signaling pathway

Alantolactone (ALA) is a sesquiterpene lactone with potent anti-inflammatory activity. However, the effect of ALA on intestinal inflammation remains largely unknown. The present study demonstrated that ALA significantly ameliorated the clinical symptoms of dextran sulfate sodium (DSS)-induced mice colitis as determined by body weight loss, diarrhea, colon shortening, inflammatory infiltration and histological injury. In mice exposed to DSS, ALA treatment significantly lowered pro-inflammatory mediators, including nuclear factor-kappa B (NF-kappa B) activation. In vitro, ALA inhibited NF-kappa B nuclear translocation and dose-dependently activated human/mouse pregnane X receptor (PXR), a key regulator gene in inflammatory bowel disease (IBD) pathogenesis. However, the pocket occluding mutants of the ligand-binding domain (LBD) of hPXR, abrogated ALA-mediated activation of the receptor. Overexpression of hPXR inhibited NF-kappa B-reporter activity and in this setting, ALA further enhanced the hPXR-mediated inhibition of NF-kappa B-reporter activity. Furthermore, silencing hPXR gene demonstrated the necessity for hPXR in downregulation of NF-kappa B activation by ALA. Finally, molecular docking studies confirmed the binding affinity between hPXR-LBD and ALA. Collectively, the current study indicates a beneficial effect of ALA on experimental IBD possibly via PXR-mediated suppression of the NF-kappa B inflammatory signaling.