The effect of proteasome inhibitor MG132 on experimental inflammatory bowel disease.
Immunoproteasome up-regulation enhances the processing of nuclear factor-kappaB (NF-kappaB) and degradation of IkappaBalpha, which correlates with increased amounts of NF-kappaB in the various cells. Aberrant activation of NF-kappaB 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)-alpha mRNA expression, epithelial cell proliferation and NF-kappaB 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-alpha mRNA expression in the colonic tissues, which was associated with suppression of NF-kappaB 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.
Inoue
S
S
Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Nakase
H
H
Matsuura
M
M
Mikami
S
S
Ueno
S
S
Uza
N
N
Chiba
T
T
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D003106:Colon / Q000473:pathology; D015853:Cysteine Proteinase Inhibitors / Q000627:therapeutic use*; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D016753:Interleukin-10 / Q000172:deficiency; D007413:Intestinal Mucosa / Q000187:drug effects / Q000473:pathology; D007976:Leupeptins / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D012333:RNA, Messenger; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D016264:Dextran Sulfate; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde