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Targeting the proteasome: partial inhibition of the proteasome by bortezomib or deletion of the immunosubunit LMP7 attenuates experimental colitis
  1. Nicole Schmidt1,
  2. Erik Gonzalez1,
  3. Alexander Visekruna2,
  4. Anja A Kühl3,
  5. Christoph Loddenkemper3,
  6. Hans Mollenkopf1,
  7. Stefan H E Kaufmann1,
  8. Ulrich Steinhoff1,
  9. Thorsten Joeris1
  1. 1Max-Planck Institute for Infection Biology, Berlin, Germany
  2. 2Institut für Medizinische Mikrobiologie, Philipps Universität, Marburg, Germany
  3. 3Campus Benjamin Franklin, Charité Berlin, Germany
  1. Correspondence to Ulrich Steinhoff, Max-Planck Institute for Infection Biology, Charitéplatz 1, D-10117 Berlin, Germany; steinhoff{at}mpiib-berlin.mpg.de

Abstract

Background and aims 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 inflammation in colitis.

Methods This concept was assessed in two different experimental set-ups. Development of dextran sodium sulfate (DSS)-induced colitis was tested (1) in lmp7−/− mice lacking the immunoproteasome subunit LMP7 and (2) in wild-type (WT) mice treated with the proteasome inhibitor bortezomib.

Results Compared with WT mice, lmp7−/− mice develop significantly attenuated colitis due to reduced nuclear factor-κB (NF-κB) signalling in the absence of LMP7. Further, treatment with bortezomib revealed dose-dependent amelioration of DSS-induced inflammation. In both approaches modulation of the proteasome activity limited the secretion of proinflammatory cytokines and chemokines. Consequently, infiltration of the colon by neutrophils and expansion of inflammatory T helper 1 (Th1) and Th17 T cells was diminished and thus prevented excessive tissue damage.

Conclusions It was demonstrated that modulation of the proteasome activity is effective in attenuating experimental colitis. The results reveal that reduction of the proteasome activity either by partial inhibition with bortezomib or by specifically targeting the immunoproteasome subunit LMP7 is a suitable treatment of intestinal inflammation.

  • Basic sciences
  • bortezomib
  • experimental colitis
  • IBD basic research
  • immunology
  • inflammation
  • inflammatory bowel disease
  • LMP7
  • proteasome

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Footnotes

  • US and TJ contributed equally to this work.

  • Funding This work was funded by the DFG within the projects SFB633 and SFB650.

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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