A novel NF-κB inhibitor, dehydroxymethylepoxyquinomicin, ameliorates inflammatory colonic injury in mice.
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.


OBJECTIVE
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.


CONCLUSIONS
DHMEQ ameliorated experimental colitis in mice. These results indicate that DHMEQ appears to be an attractive therapeutic agent for IBD.
Department of General Surgery, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
Tohru
T
Funakoshi
Kenichiro
K
Yamashita
Nobuki
N
Ichikawa
Moto
M
Fukai
Tomomi
T
Suzuki
Ryoichi
R
Goto
Tetsu
T
Oura
Nozomi
N
Kobayashi
Takehiko
T
Katsurada
Shin
S
Ichihara
Michitaka
M
Ozaki
Kazuo
K
Umezawa
Satoru
S
Todo
D000818:Animals; D001549:Benzamides / Q000494:pharmacology* / Q000627:therapeutic use*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects; D018932:Chemokine CCL2 / Q000187:drug effects / Q000378:metabolism; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003512:Cyclohexanones / Q000494:pharmacology* / Q000627:therapeutic use*; D016207:Cytokines / Q000187:drug effects* / Q000378:metabolism*; D016264:Dextran Sulfate; D019073:HT29 Cells; D006801:Humans; D053762:Interleukin-12 Subunit p40 / Q000187:drug effects / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D053583:Interleukin-1beta / Q000187:drug effects / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000187:drug effects / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D014302:Trinitrobenzenesulfonic Acid; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism
D001549:Benzamides; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D003512:Cyclohexanones; D016207:Cytokines; D053762:Interleukin-12 Subunit p40; D020381:Interleukin-17; D053583:Interleukin-1beta; D015850:Interleukin-6; D016209:Interleukin-8; D016328:NF-kappa B; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C464444:dehydroxymethylepoxyquinomicin; D014302:Trinitrobenzenesulfonic Acid; D016264:Dextran Sulfate