Ginsenosides regulate PXR/NF-kB signaling and attenuate dextran sulfate sodium-induced colitis

Abstract

Pregnane X receptor (PXR) activation exhibits anti-inflammatory effects via repressing nuclear factor-kB (NF-kB); however, its overactivation may disrupt homeostasis of various enzymes and transporters. Here we found that ginsenosides restore PXR/NFkB signaling in inflamed conditions without disrupting PXR function in normal conditions. The effects and mechanisms of ginsenosides in regulating PXR/NF-kB signals were determined both in vitro and in vivo. Ginsenosides significantly inhibited NFkB activation and restored the expression of PXR target genes in tumor necrosis factor-a-stimulated LS174T cells. Despite not being PXR agonists, ginsenosides repressed NF-kB activation in a PXR-dependent manner. Ginsenosides significantly increased the physical association between PXR and the NF-kB p65 subunit and thereby decreased the nuclear translocation of p65. Ginsenoside Rb1 and compound K (CK) were major bioactive compounds in the regulating PXR/NF-kB signaling. Consistently, ginsenosides significantly attenuated dextran sulfate sodium-induced experimental colitis, which was associated with restored PXR/NF-kB signaling. This study indicates that ginsenosides may elicit antiinflammatory effects via targeting PXR/NF-kB interaction without disrupting PXR function in healthy conditions. Ginsenoside Rb1 and CK may serve as leading compounds in the discovery of new drugs that target PXR/NF-kB interaction in therapy for inflammatory bowel disease.