RRC ID 18165
Author Funakoshi T, Yamashita K, Ichikawa N, Fukai M, Suzuki T, Goto R, Oura T, Kobayashi N, Katsurada T, Ichihara S, Ozaki M, Umezawa K, Todo S.
Title A novel NF-κB inhibitor, dehydroxymethylepoxyquinomicin, ameliorates inflammatory colonic injury in mice.
Journal J Crohns Colitis
Abstract BACKGROUND:In inflammatory bowel disease (IBD), gut inflammation is associated with the activation of nuclear factor kappa B (NF-κB), a key pro-inflammatory transcription factor.
AIM:To investigate the therapeutic potential of a novel, specific NF-κB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), we examined its effect on IBD using murine experimental colitis models.
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 pro-inflammatory cytokines in the colonic tissues.
RESULTS:In RAW264.7 cells, DHMEQ significantly inhibited tumour necrosis factor (TNF)-α and interleukin (IL)-6 production induced by LPS in a dose-dependent manner by blocking the nuclear translocation of NF-κB. 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-1β, TNF-α, 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.
CONCLUSION:DHMEQ ameliorated experimental colitis in mice. These results indicate that DHMEQ appears to be an attractive therapeutic agent for IBD.
Volume 6(2)
Pages 215-25
Published 2012-3
DOI 10.1016/j.crohns.2011.08.011
PII S1873-9946(11)00215-7
PMID 22325176
MeSH Animals Benzamides / pharmacology* Benzamides / therapeutic use* CD4-Positive T-Lymphocytes / drug effects Chemokine CCL2 / drug effects Chemokine CCL2 / metabolism Colitis / chemically induced Colitis / drug therapy* Colitis / metabolism Colitis / pathology Cyclohexanones / pharmacology* Cyclohexanones / therapeutic use* Cytokines / drug effects* Cytokines / metabolism* Dextran Sulfate HT29 Cells Humans Interleukin-12 Subunit p40 / drug effects Interleukin-12 Subunit p40 / metabolism Interleukin-17 / metabolism Interleukin-1beta / drug effects Interleukin-1beta / metabolism Interleukin-6 / metabolism Interleukin-8 / drug effects Interleukin-8 / metabolism Macrophages / drug effects Male Mice Mice, Inbred C57BL NF-kappa B / antagonists & inhibitors* NF-kappa B / drug effects RNA, Messenger / metabolism Trinitrobenzenesulfonic Acid Tumor Necrosis Factor-alpha / drug effects Tumor Necrosis Factor-alpha / metabolism
IF 7.827
Times Cited 39
Human and Animal Cells RAW 264 (RCB0535)