title: Targeting the proteasome: partial inhibition of the proteasome by bortezomib or deletion of the immunosubunit LMP7 attenuates experimental colitis.
abstract: OBJECTIVE
  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-kappaB (NF-kappaB) 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.
authors.affiliation: Max-Planck Institute for Infection Biology, Charitéplatz 1, Berlin, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Schmidt
authors.forename: Erik
authors.initials: E
authors.lastname: Gonzalez
authors.forename: Alexander
authors.initials: A
authors.lastname: Visekruna
authors.forename: Anja A
authors.initials: AA
authors.lastname: Kühl
authors.forename: Christoph
authors.initials: C
authors.lastname: Loddenkemper
authors.forename: Hans
authors.initials: H
authors.lastname: Mollenkopf
authors.forename: Stefan H E
authors.initials: SH
authors.lastname: Kaufmann
authors.forename: Ulrich
authors.initials: U
authors.lastname: Steinhoff
authors.forename: Thorsten
authors.initials: T
authors.lastname: Joeris
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D001897:Boronic Acids / Q000627:therapeutic use*; D000069286:Bortezomib; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D018928:Immunity, Mucosal; D018836:Inflammation Mediators / Q000378:metabolism; D020381:Interleukin-17 / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D009097:Multienzyme Complexes / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism; D020556:Neutrophil Infiltration; D011480:Protease Inhibitors / Q000627:therapeutic use*; D046988:Proteasome Endopeptidase Complex; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000627:therapeutic use*; D015398:Signal Transduction / Q000502:physiology; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001897:Boronic Acids; D018836:Inflammation Mediators; D020381:Interleukin-17; D009097:Multienzyme Complexes; D016328:NF-kappa B; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D016264:Dextran Sulfate; C077436:LMP7 protein; D046988:Proteasome Endopeptidase Complex