Unknown,Transcriptomics,Genomics,Proteomics

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Subunit-specific vs. non-selective proteasome modulation in limiting inflammation in experimental colitis

ABSTRACT: Inflammatory bowel disease (IBD), comprising CrohnM-BM-4s disease and Ulcerative colitis, is characterized by chronic relapsing inflammation of the gut. It has been shown that increased proteasomal activity is associated with the expression of immunoproteasomes, which enhances NF-kB activation and thus promotes inflammation in IBD-patients. Here, we investigate whether modulation of the proteasomal activity is a suitable therapeutic approach to limit inflammation in colitis. This concept was tested in two different experimental setups. First, development of dextran sulfate sodium (DSS)-induced colitis was tested in lmp7-/--mice, which lack the essential immunoproteasome-subunit LMP7 or in wildtype-mice treated with the proteasome inhibitor bortezomib. Compared to WT mice, lmp7-/- mice revealed significantly attenuated colitis resulting from reduced NF-kB activation in the absence of LMP7. Further, treatment with bortezomib revealed dose-dependent amelioration of DSS-induced inflammation. In both approaches proteasome modulation limited the infiltration of neutrophils, consequently reducing tissue damage. In summary our experiments demonstrate that modulation of the proteasomal activity is effective in attenuating experimental colitis. In particular, our data suggest that the immunoproteasome-subunit LMP7 is a suitable target for the therapy of IBD. Microarray experiments were performed as dual-color hybridizations. To compensate for dye-specific effects, a dye-reversal color-swap was applied. Samples of proximal colon were cut longitudinally, washed in PBS, shortly incubated in 4M Guanidinium-isothiocyanat and transferred to TRIzol (Invitrogen).

ORGANISM(S): Mus musculus

SUBMITTER: Hans-Joachim Mollenkopf

PROVIDER: E-GEOD-18163 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Targeting the proteasome: partial inhibition of the proteasome by bortezomib or deletion of the immunosubunit LMP7 attenuates experimental colitis.

Schmidt Nicole N Gonzalez Erik E Visekruna Alexander A Kühl Anja A AA Loddenkemper Christoph C Mollenkopf Hans H Kaufmann Stefan H E SH Steinhoff Ulrich U Joeris Thorsten T

Gut 20100701 7

<h4>Background and aims</h4>Inflammatory bowel disease (IBD), comprising Crohn s disease and ulcerative colitis, is characterised by chronic relapsing inflammation of the gut. Increased proteasome activity, associated with the expression of immunoproteasomes, was found to enhance proinflammatory signalling and thus promotes inflammation in patients with IBD. The aim of this study was to explore whether modulation of the proteasomal activity is a suitable therapeutic approach to limit inflammatio ...[more]

PMID: 20581238

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Dataset Information

Subunit-specific vs. non-selective proteasome modulation in limiting inflammation in experimental colitis

Publications

Targeting the proteasome: partial inhibition of the proteasome by bortezomib or deletion of the immunosubunit LMP7 attenuates experimental colitis.

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