Ulcerative Colitis: Joeris T

Visekruna A, Joeris T, Schmidt N, Lawrenz M, Ritz JP, Buhr HJ, Steinhoff U. · Department of Surgery I, Charité-Medical School, Campus Benjamin Franklin, Berlin, Germany. · Inflamm Bowel Dis. · Pubmed #19067411 No free full text.

Abstract: BACKGROUND: The diagnostic differentiation between Crohn's disease (CD) and ulcerative colitis (UC) is sometimes difficult. To date, there are no serological markers that are specific and sensitive enough to differentiate between these 2 diseases. Early and safe prediction of the inflammatory bowel disease (IBD) type is of great importance for the specific treatment of IBD patients. We thus analyzed and compared the expression of catalytic proteasome subunits in the gut of mice and in the normal and inflamed intestines of CD and UC patients and assessed whether the subunit pattern is suitable for diagnostic differentiation. METHODS: The 20S proteasomes were isolated from surgical tissue specimens derived from terminal ileum and colon of IBD patients and controls. Spots of 20S proteasomes separated by 2D electrophoresis were analyzed by mass spectrometry. Quick detection of catalytic beta2, beta2i, and beta5i subunits was performed by incubating proteasomes with a biotinylated inhibitor (AdaK(Bio)Ahx3L3VS) and subsequently by streptavidin-horseradish peroxide. RESULTS: 20S proteasomes were isolated from the human liver, colon, and terminal ileum. Low expression of the immunosubunits beta1i and beta2i was found in the liver and colon but high amounts in the small intestine. In colon and liver beta5i was found to be associated with the constitutive beta1, beta2 subunits, indicating the existence of mixed proteasomes. Further, inflammation in CD but not UC patients induced massive upregulation of beta1i and beta2i in the colon and terminal ileum, indicating the importance of this protein complex as a disease marker. CONCLUSIONS: We here show that CD and UC patients display a characteristic pattern of proteasome subunit composition which can be used as diagnostic tool to differentiate between CD and UC.

Visekruna A, Joeris T, Seidel D, Kroesen A, Loddenkemper C, Zeitz M, Kaufmann SH, Schmidt-Ullrich R, Steinhoff U. · Max Planck Institute of Infection Biology, Berlin, Germany. · J Clin Invest. · Pubmed #17124531 links to  free full text

Abstract: Enhanced NF-kappaB activity is involved in the pathology of both forms of inflammatory bowel disease (IBD), Crohn disease (CD) and ulcerative colitis (UC). Here we analyzed the mechanism of proteasome-mediated NF-kappaB activation in CD and UC. Our studies demonstrate that the subunit composition and the proteolytic function of proteasomes differ between UC and CD. High expression of the immunoproteasome subunits beta1i and beta2i is characteristic of the inflamed mucosa of CD. In line with this, we found enhanced processing of NF-kappaB precursor p105 and degradation of inhibitor of NF-kappaB, IkappaBalpha, by immunoproteasomes isolated from the mucosa of CD patients. In comparison with healthy controls and CD patients, UC patients exhibited an intermediate phenotype regarding the proteasome-mediated processing/degradation of NF-kappaB components. Finally, increased expression of the NF-kappaB family member c-Rel in the inflamed mucosa of CD patients suggests that p50/c-Rel is important for IFN-gamma-mediated induction of immunoproteasomes via IL-12-driven Th1 responses. These findings suggest that distinct proteasome subunits influence the intensity of NF-kappaB-mediated inflammation in IBD patients.