A novel NF-kappa B inhibitor, dehydroxymethylepoxyquinomicin, ameliorates inflammatory colonic injury in mice

作者:Funakoshi Tohru; Yamashita Kenichiro*; Ichikawa Nobuki; Fukai Moto; Suzuki Tomomi; Goto Ryoichi; Oura Tetsu; Kobayashi Nozomi; Katsurada Takehiko; Ichihara Shin; Ozaki Michitaka; Umezawa Kazuo; Todo Satoru
来源:JOURNAL OF CROHNS %26 COLITIS, 2012, 6(2): 215-225.
DOI:10.1016/j.crohns.2011.08.011

摘要

Background: In inflammatory bowel disease (IBD), gut inflammation is associated with the activation of nuclear factor kappa B (NE-kappa B), a key pro-inflammatory transcription factor. %26lt;br%26gt;Aim: To investigate the therapeutic potential of a novel, specific NE-kappa B inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), we examined its effect on IBD using murine experimental colitis models. %26lt;br%26gt;Methods: The in vitro effect of DHMEQ was evaluated by inflammatory cytokine production and p65 immunostaining using HT-29 and RAW264.7 cells. The in vivo therapeutic effect of DHMEQ was studied in colitis induced by dextran sulphate sodium (DSS) and trinitrobenzenesulphonic acid (TNBS). In these, progression and severity of colitis was mainly assessed by the disease activity index (DAI), histopathology, cellular infiltration, and mRNA expression levels of proinflammatory cytokines in the colonic tissues. %26lt;br%26gt;Results: In RAW264.7 cells, DHMEQ significantly inhibited tumour necrosis factor (TNF)-alpha and interleukin (IL)-6 production induced by LPS in a dose-dependent manner by blocking the nuclear translocation of NE-kappa B. In addition, DHMEQ inhibited IL-8 production induced by LPS in HT-29 cells. DHMEQ significantly ameliorated DSS colitis as assessed by DAI scores, colonic oedema, and histological scores. Immunohistochemistry revealed that DHMEQ inhibited colonic infiltration of nuclear p65(+) cells, CD4(+) lymphocytes, and F4/80(+) macrophages. mRNA expression levels of the pro-inflammatory cytokines, such as IL-1 beta, TNF-alpha, IL-6, IL-12p40, IL-17, and MCP-1 were also suppressed by DHMEQ administration. Furthermore, DHMEQ significantly ameliorated TNBS colitis as assessed by body-weight changes and histological scores. %26lt;br%26gt;Conclusion: DHMEQ ameliorated experimental colitis in mice. These results indicate that DHMEQ appears to be an attractive therapeutic agent for IBD.

  • 出版日期2012-3