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

Dichotomal effect of space flight-associated microgravity on stress-activated protein kinases in innate immunity

Space flight strongly moderates human immunity but is in general well tolerated. Elucidation of the mechanisms by which zero gravity interacts with human immunity may provide clues for developing rational avenues to deal with exaggerated immune responses, e.g. as in autoimmune disease. Using two sounding rockets and one manned Soyuz launch, the influence of space flight on immunological signal transduction provoked by lipopolysaccharide (LPS) stimulation was investigated in freshly isolated peripheral blood monocytes and was compared to samples obtained from on-board centrifuge-loaded 1a'...g controls. The effect of microgravity on immunological signal transduction is highly specific, since LPS dependent Jun-N-terminal kinase activation is impaired in the 0a'...g condition, while the corresponding LPS dependent activation of p38 MAP kinase remains unaffected. Thus our results identify Jun-N-terminal kinase as a relevant target in immunity for microgravity and support using Jun-N-terminal kinase specific inhibitors for combating autoimmune disease

Suppression of airway inflammation by Illicium verum and trans-anethole

_Background_ SH2 domain containing inositol-5-phosphatase (SHIP1) is an important modulator of innate and adaptive immunity. In mice, loss of SHIP1 provokes severe ileitis resembling Crohn's disease (CD), as a result of deregulated immune responses, altered cytokine production and intestinal fibrosis. Recently, SHIP1 activity was shown to be correlated to the presence of a CD-associated single nucleotide polymorphism in ATG16L1. Here, we studied SHIP1 activity and expression in an adult cohort of CD patients. _Methods_ SHIP1 activity, protein and mRNA expression in peripheral blood mononuclear cells from CD patients in clinical remission were determined by Malachite green assay, Western blotting an

Pregnane X receptor activation constrains mucosal NF-κB activity in active inflammatory bowel disease

Background The Pregnane X Receptor (PXR) is a principal signal transducer in mucosal responses to xenobiotic stress. It is well-recognized that inflammatory bowel disease is accompanied by xenobiotic stress, but the importance of the PXR in limiting inflammatory responses in inflammatory bowel disease remains obscure at best. Methods We stimulate a total of 106 colonic biopsies from 19 Crohn’s disease patients with active disease, 36 colonic biopsies from 8 control patients, colonic organo