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Proteasome-mediated degradation of IκBα and processing of p105 in Crohn disease and ulcerative colitis
Alexander Visekruna, … , Ruth Schmidt-Ullrich, Ulrich Steinhoff
Alexander Visekruna, … , Ruth Schmidt-Ullrich, Ulrich Steinhoff
Published December 1, 2006
Citation Information: J Clin Invest. 2006;116(12):3195-3203. https://doi.org/10.1172/JCI28804.
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Research Article Gastroenterology Article has an altmetric score of 1

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

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Abstract

Enhanced NF-κB 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-κB 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 β1i and β2i is characteristic of the inflamed mucosa of CD. In line with this, we found enhanced processing of NF-κB precursor p105 and degradation of inhibitor of NF-κB, IκBα, 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-κB components. Finally, increased expression of the NF-κB family member c-Rel in the inflamed mucosa of CD patients suggests that p50/c-Rel is important for IFN-γ–mediated induction of immunoproteasomes via IL-12–driven Th1 responses. These findings suggest that distinct proteasome subunits influence the intensity of NF-κB–mediated inflammation in IBD patients.

Authors

Alexander Visekruna, Thorsten Joeris, Daniel Seidel, Anjo Kroesen, Christoph Loddenkemper, Martin Zeitz, Stefan H.E. Kaufmann, Ruth Schmidt-Ullrich, Ulrich Steinhoff

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Figure 7

Proteasome inhibitor secreted by probiotic bacteria inhibits the chymotrypsin-like activity of 20S proteasomes isolated from CD patients and prevents nascent colitis in IL-10 KO mice.

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Relative expression of proteasomal immunosubunits in Caco-2 cells.
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(A) The chymotrypsin-like activity of 20S proteasomes (2 μg) purified from CD patients (n = 6) was measured in the presence (50 μl) or absence of conditioned media from probiotic bacteria (VSL#3) and E. coli strain Nissle 1917. As control, the synthetic proteasome inhibitor MG132 was used at a concentration of 10 μM. (B) IL-10 KO mice were treated before the onset of colitis either with PBS- (control) or VSL#3-conditioned medium. Treatment started at the age of 10 weeks and was performed for 3 weeks by giving either 500 μl PBS or VSL#3 intragastrically every other day. Weight was monitored for both groups (n = 8).

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