effect of proteasome inhibitor MG132 on experimental inflammatory bowel disease

• Published in: Clinical and experimental immunology 2009-04, Vol.156 (1), p.172-182
• Main Authors: Inoue, S, Nakase, H, Matsuura, M, Mikami, S, Ueno, S, Uza, N, Chiba, T
• Format: Article
• Language: English
• Subjects: Analytical, structural and metabolic biochemistry; Animal Studies; Animals; Biological and medical sciences; Cell Proliferation - drug effects; Colon - pathology; Cysteine Proteinase Inhibitors - therapeutic use; Dextran Sulfate; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical - methods; epithelial regeneration; Female; Fundamental and applied biological sciences. Psychology; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression Regulation - drug effects; IBD; Inflammatory Bowel Diseases - drug therapy; Inflammatory Bowel Diseases - immunology; Inflammatory Bowel Diseases - pathology; Interleukin-10 - deficiency; Intestinal Mucosa - drug effects; Intestinal Mucosa - pathology; Leupeptins - therapeutic use; MDR1; Medical sciences; Mice; Mice, Inbred C57BL; NF-κB; Other diseases. Semiology; proteasome inhibitor; RNA, Messenger - genetics; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Transcription Factor RelA - metabolism; Tumor Necrosis Factor-alpha - biosynthesis; Tumor Necrosis Factor-alpha - genetics
• ISSN: 0009-9104; 1365-2249
• DOI: 10.1111/j.1365-2249.2008.03872.x

Immunoproteasome up-regulation enhances the processing of nuclear factor-κB (NF-κB) and degradation of IκBα, which correlates with increased amounts of NF-κB in the various cells. Aberrant activation of NF-κB is involved in the pathogenesis of inflammatory bowel disease (IBD). The aim of this study was to elucidate the effect of proteasome inhibitor MG132 on experimental IBD. We investigated the effects of MG132 on intestinal inflammation and epithelial regeneration in both interleukin-10-deficient (IL-10⁻/⁻) mice and mice with dextran sulphate sodium (DSS)-induced colitis. Body weight, histological findings and tumour necrosis factor (TNF)-α mRNA expression, epithelial cell proliferation and NF-κB p65 activity in colonic tissues were examined. The effects of MG132 on cell proliferation, migration and multiple drug resistance 1 (MDR1) gene expression were determined in vitro. MG132 ameliorated intestinal inflammation of IL-10⁻/⁻ mice by decreasing TNF-α mRNA expression in the colonic tissues, which was associated with suppression of NF-κB activation, and reduced significantly the number of Ki-67-positive intestinal epithelial cells. On the other hand, MG132 did not reduce intestinal inflammation in mice with DSS-induced colitis, and delayed significantly the recovery of body weight and epithelial regeneration. MG132 also suppressed significantly epithelial cell proliferation, cell migration and MDR1 gene expression in vitro. Proteasome inhibition reduces T cell-mediated intestinal inflammation, but may interrupt both epithelial regeneration and barrier function of colonic mucosa. Optimal use of proteasome inhibitor should be kept in mind when we consider its clinical application for patients with IBD.