Xenobiotic Receptor PXR-Mediated Resistance to Salmonella Invasion and Its Mechanism
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Pregnane X receptor (PXR) is a ligand-activated nuclear receptor that regulates gene expression of the metabolizing enzymes that are involved in detoxification of endogenous and exogenous compounds in the gastrointestinal (GI) tract. In recent years, PXR has been found to have novel functions in maintenance of homeostasis of the GI tract, as mice deficient in PXR have spontaneous intestinal inflammation. Because the GI tract homeostasis is maintained through interactions between microbiota and host intestinal cells, we investigated the role of PXR in regulating the susceptibility of the colon cells to Salmonella infection. Using PXR-transfected HCT116 and HT29 cell lines we found that PXR transfected cells were resistant to the Salmonella infection and the resistance was dependent on the PXR activation by the typical PXR agonists rifampicin (RIF) and hyperforin. Furthermore, the ligand-dependent resistance could be antagonized by the PXR antagonist ketoconazole, confirming the role of PXR in resistance. In an earlier study, we found NF-B activation by LPS to inhibit PXR activity, and, consistent with the observation, LPS treatment of the cells weakened the resistance of the PXR-transfected cells to Salmonella infection. To understand the mechanism of the PXR-regulated resistance, we analyzed the role of PXR in regulating the intestinal barrier gene expressions such as occludin, ZO-1, and claudin, and found that occludin expression was significantly up-regulated by the PXR activation. Taken together, our results suggest that PXR plays a role in regulating GI tract resistance to pathogenic bacterial infection and provides a potential therapeutic approach for treatment of Salmonella infection.
Wang, Meichen (2016). Xenobiotic Receptor PXR-Mediated Resistance to Salmonella Invasion and Its Mechanism. Master's thesis, Texas A & M University. Available electronically from