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P041. Pregnane X receptor is an unlikely therapeutic target for inflammatory bowel disease

J. Deuring, C. de Haar, E.J. Kuipers, M. Peppelenbosch, C.J. van der Woude

Erasmus MC, Rotterdam, The Netherlands

Background and Aim: Therapy for inflammatory bowel disease (IBD) is concentrated on reducing mucosal inflammation. Detoxification of various anti-inflammatory drugs is mediated by nuclear receptors like the Pregnane X Receptor (PXR). Interestingly, PXR activation is also associated with down regulation of nuclear factor kappa B (NF-kB) target genes, which are involved in inflammatory processes. Here we studied the PXR expression and function in inflamed and non-inflamed intestinal epithelium cells.

Methods: Small bowel biopsies from healthy individuals (n = 27), inactive (n = 9) and active Crohns disease (n = 25) patients, together with colon biopsies from other healthy individuals (n = 10), inactive (n = 67) and active IBD (n = 55) were stained immunohistochemically for PXR expression. The mRNA expression of PXR target gene; CYP3A4 and NF-kB target genes; iNOS and IL8 were measured in freshly isolated colon biopsies from healthy controls (n = 4), inactive (n = 8) and active IBD (n = 8) patients as well as the intestinal cancer cell line LS174t after stimulation with TNFa, E. Coli lysate and PXR ligand rifampicin.

Results: Low PXR expression was seen histochemically in small bowel healthy individuals, inactive and active Crohns disease. The same low PXR expression was detected in colonic biopsies from all three groups. In the intestinal epithelial cells that stained positive for PXR, only cytoplasmic expression was seen. In addition, low PXR mRNA expression was found on colon biopsies from healthy individuals as well as from IBD patients. Stimulation of LS174t cells with a combination of pro-inflammatory compounds and rifampicin, led to a reduction in expression of iNOS and IL8 and an increased expression of CYP3A4.

Conclusion: Mucosal biopsies, with or without active inflammation, express low levels of PXR protein and mRNA. Accordingly, the use of PXR ligands as a therapeutic target for IBD by reduction of NF-kB target genes is questionable. Increasing the mucosal expression of PXR in combination with PXR-ligands is therefore an interesting therapeutic target.