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Proteasome-mediated degradation of IkappaBalpha and processing of p105 in Crohn disease and ulcerative colitis

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Official URL:https://doi.org/10.1172/JCI28804
PubMed:View item in PubMed
Creators Name:Visekruna, A. and Joeris, T. and Seidel, D. and Kroesen, A. and Loddenkemper, C. and Zeitz, M. and Kaufmann, S.H.E. and Schmidt-Ullrich, R. and Steinhoff, U.
Journal Title:Journal of Clinical Investigation
Journal Abbreviation:J Clin Invest
Page Range:3195-3203
Date:December 2006
Keywords:Western Blotting, Caco-2 Cells, Ulcerative Colitis, Crohn Disease, Gene Expression, I-kappa B Proteins, Interferon Type II, Interleukin-12, Intestinal Mucosa, Inbred C57BL Mice, Biological Models, NF-kappa B p50 Subunit, Proteasome Endopeptidase Complex, Protein Subunits, Proto-Oncogene Proteins c-rel, Reverse Transcriptase Polymerase Chain Reaction, Matrix-Assisted Laser Desorption-Ionization Mass Spectrometry, Tumor Necrosis Factor-alpha, Animals, Mice
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.
Publisher:American Society for Clinical Investigation (U.S.A.)
Item Type:Article

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