The role of intestinal epithelium in inflammatory bowel disease and inflammation related intestinal cancer

The intestinal epithelial cells(IEC) are indispensable factors in the host protection against the harmful luminal content. In this thesis we aimed to gain further insight in the role of IEC in the Inflammatory Bowel Disease(IBD) aetiology, since it is an important mediator between the already known factors that give onset of IBD. To investigate the IEC involvement in IBD we stimulated freshly isolated biopsies from CD patients with PXR ligands to inhibit the NF-κB(inflammatory key regulator) signalling. We have found that the presence of PXR was more important than the actual PXR activation to inhibit the NF-κB activity. It becomes increasingly clear that the function of PXR goes beyond its primary function in the xenobiotic detoxification pathways. We found that high PXR expression is present exclusively in the neoplastic intestinal epithelium, whereas no PXR protein could be detected in normal or inflamed intestinal tissue. In vitro experiments uncovered that this high PXR expression reduces the growth speed of the cells but increases the high cell density survival. Proper functioning IEC are depending on correctly folded (inside the endoplasmic reticulum(ER)) and expressed proteins. We postulate that inflammation related conditions affect ER-dependent proteins in expression, e.g. ABCG2 and initiate ER-stress. As such, ABCG2 expression and function is impeded due to ER-protein folding difficulties. Besides, ER stress in Paneth cells is found in a subset of CD patients carrying an ATG16L1 risk allele(G). This indicates that multiple factors IBD related factors can provoke protein-folding difficulties. Overall we conclude that, the intestinal epithelium has a distinct function in the aetiology of IBD patients on many disease-associated factors. This thesis justifies the extensive investigation of IEC driven therapeutic approaches for IBD patients.