Prevention of Experimental Colitis by a Selective Inhibitor of the Immunoproteasome

被引:197
作者
Basler, Michael [1 ,2 ]
Dajee, Maya [4 ]
Moll, Carlo [3 ]
Groettrup, Marcus [1 ,2 ]
Kirk, Christopher J. [4 ]
机构
[1] Univ Constance, Div Immunol, Dept Biol, D-78457 Constance, Germany
[2] Univ Constance, Biotechnol Inst Thurgau, Kreuzlingen, Switzerland
[3] Cantonal Hosp Munsterlingen, Inst Pathol, Munsterlingen, Switzerland
[4] Proteolix Inc, San Francisco, CA 94080 USA
基金
瑞士国家科学基金会; 美国国家科学基金会;
关键词
INFLAMMATORY-BOWEL-DISEASE; PROTEASOME INHIBITORS; ULCERATIVE-COLITIS; 20S PROTEASOME; EXPRESSION; MICE; PROTEOLYSIS; IL-23; TRANSCRIPTION; DEGRADATION;
D O I
10.4049/jimmunol.0903182
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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 (beta 1i), multicatalytic endopeptidase complex-like-1 (beta 2i), and LMP7 (beta 5i), 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-1 beta, 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. The Journal of Immunology, 2010, 185: 634-641.
引用
收藏
页码:634 / 641
页数:8
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