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P054. Pregnane X Receptor as a therapeutic target for inflammatory bowel disease

J. Deuring1, T. van den Berg2, E. Kuipers1, M.P. Peppelenbosch3, C. de Haar4, C.J. van der Woude2

1Erasmus Medical Center, Rotterdam, Netherlands; 2Erasmus Medical Center, Department of Gastroenterology & Hepatology, Rotterdam, Netherlands; 3Erasmus Medical Center, Department of Gastroenterology and Hepatology, Rotterdam, Netherlands; 4Erasmus Medical Center, Gastroenterology and Hepatology, Rotterdam, Netherlands

Background: Mucosal detoxification of various anti-inflam­matory drugs is mediated amongst others by nuclear receptors like the Pregnane X Receptor (PXR). The activation of PXR is associated with down regulation of nuclear-factor κ‑B (NF-κB) activity, which plays a key role in inflammation. Here, we studied whether PXR activation could reduce NF-κB-mediated inflammatory responses in intestinal biopsies from inflammatory bowel disease (IBD) patients.

Methods: Three biopsies were taken from four different bowel locations in IBD (n = 24) and control patients (n = 6). Biopsies from endoscopically inflamed and non-inflamed areas were included and inflammation was histologically confirmed by an expert pathologist. The biopsies were cultured for 18 h with or without PXR activator Rifampicin (100 µM). Rifampicin-induced PXR activation was verified by the mRNA expression of PXR target genes (Cyp3A4, Sult1a, MDR1) and the possible repression of NF-κB by the expression of its target genes (IL‑8, IL‑1β, TNFα). In addition, the protein expression of TNFα and IL‑8 in biopsy homogenates was measured using ELISA.

Results: The gene expression of Sult1a and MDR1 are up-regulated in all the biopsies after Rifamipcin stimulation. Furthermore, the expression of IL‑8 (p < 0.001) and IL‑1β (p < 0.01) are 10–100 fold higher in biopsies from IBD patients than in biopsies from control patients, irrespective of disease activity. However, this elevated cytokine expression was significantly reduced after Rifampicin stimulation (p < 0.01). This reduction is observed in all biopsies on mRNA as well as protein expression and is regardless of intestinal-location.

Conclusions: Rifampicin can activate PXR in human intestinal biopsies. Biopsies taken from IBD patients have higher NF-κB activity than the biopsies taken from control patients. Nevertheless, this high NF-κB activity could be reduced by Rifampicin, irrespective of disease type. Thus, PXR activation by Rifampicin could be used as a therapeutic approach to reduce mucosal inflammation in patients with IBD.