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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Blotting, Western
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Caco-2 Cells
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Cell Line
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Colitis, Ulcerative / metabolism*
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Colitis, Ulcerative / pathology
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Crohn Disease / metabolism*
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Crohn Disease / pathology
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Gene Expression / drug effects
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Humans
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I-kappa B Proteins / metabolism*
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Interferon-gamma / metabolism
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Interferon-gamma / pharmacology
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Interleukin-12 / metabolism
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Intestinal Mucosa / metabolism
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Mice
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Mice, Inbred C57BL
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Models, Biological
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NF-KappaB Inhibitor alpha
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NF-kappa B p50 Subunit / metabolism*
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Proteasome Endopeptidase Complex / genetics
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Proteasome Endopeptidase Complex / metabolism*
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Proteasome Inhibitors
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Protein Subunits / genetics
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Protein Subunits / metabolism
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Proto-Oncogene Proteins c-rel / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
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Tumor Necrosis Factor-alpha / metabolism
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Tumor Necrosis Factor-alpha / pharmacology
Substances
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I-kappa B Proteins
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NF-kappa B p50 Subunit
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NFKB1 protein, human
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NFKBIA protein, human
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Nfkbia protein, mouse
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Proteasome Inhibitors
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Protein Subunits
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Proto-Oncogene Proteins c-rel
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Tumor Necrosis Factor-alpha
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NF-KappaB Inhibitor alpha
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Interleukin-12
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Interferon-gamma
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Proteasome Endopeptidase Complex