Prevention of experimental colitis by a selective inhibitor of the immunoproteasome.
The proteasome, a multicatalytic protease, is responsible for the degradation of intracellular proteins. Stimulation of cells with inflammatory cytokines, such as IFN-gamma, leads to the replacement of the constitutive catalytic proteasome subunits by the inducible subunits low molecular mass polypeptide (LMP)2 (beta1i), multicatalytic endopeptidase complex-like-1 (beta2i), and LMP7 (beta5i), which are required for the production of certain MHC class I-restricted T cell epitopes. In this study, we investigated the effect of immunoproteasomes on the development of dextran sulfate sodium-induced colitis. Colitis induction in LMP2-, LMP7-, and multicatalytic endopeptidase complex-like-1-deficient mice caused reduced weight loss compared with wild-type mice. Although colon lengths were shortened in wild-type mice, no reduction was observed in immunoproteasome-deficient mice. In accordance with this, proinflammatory cytokines, such as TNF-alpha and IL-1beta, were not upregulated in these mice. Blockage of LMP7 by a novel LMP7-selective inhibitor (PR-957) strongly reduced pathological symptoms of dextran sulfate sodium-induced colitis. Production of numerous cytokines in PR-957-treated mice was suppressed, resulting in reduced inflammation and tissue destruction. Taken together, these results demonstrate that an immunoproteasome-specific inhibitor can be used to attenuate autoimmune diseases like colitis.
Basler
Michael
M
Division of Immunology, Department of Biology, University of Constance, Konstanz, Germany. michael.basler@uni-konstanz.de
Dajee
Maya
M
Moll
Carlo
C
Groettrup
Marcus
M
Kirk
Christopher J
CJ
D000818:Animals; D001327:Autoimmune Diseases / Q000201:enzymology / Q000517:prevention & control; D003093:Colitis, Ulcerative / Q000201:enzymology / Q000276:immunology* / Q000517:prevention & control*; D004195:Disease Models, Animal; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009842:Oligopeptides / Q000008:administration & dosage* / Q000627:therapeutic use; D046988:Proteasome Endopeptidase Complex / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D061988:Proteasome Inhibitors; D015854:Up-Regulation / Q000276:immunology
D009842:Oligopeptides; C542291:PR-957; D061988:Proteasome Inhibitors; C077436:LMP7 protein; D046988:Proteasome Endopeptidase Complex