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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 6

Effect of immunoproteasomes on degradation of IκBα.

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Proteasome inhibitor secreted by probiotic bacteria inhibits the chymotr...
(A) Kinetics of IκBα degradation by 20S proteasomes purified from colonic mucosa of patients with IBD and controls (CD, n = 5; UC, n = 5; controls, n = 5). IκBα was in vitro translated in the presence of 35S-methionine (Supplemental Figure 2) and incubated with isolated 20S proteasomes for indicated times. C60 represents a control incubated for 60 minutes without 20S proteasomes with an equivalent amount of IκBα. (B) Quantitative evaluation of IκBα degradation by 20S proteasomes isolated from patients with IBD and controls in the absence of ATP. P < 0.0001 (by 1-way ANOVA); n = 5. (C) Analysis of degradation of in vitro–translated IκBα by 2 different subsets of 20S proteasomes. Data from 1 representative experiment are shown for purified constitutive proteasomes (LCL 721.174; n = 3) and immunoproteasomes (LCL 721; n = 3). Lack of β1i and β5i in LCL 721.174 excludes the incorporation of immunosubunits in 20S proteasomes. C90 represents a control line without 20S proteasomes. (D) Quantification of IκBα degradation by 20S protesomes isolated from LCL 721 and LCL 721.174 cells (n = 3).

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