Anti-colitis and -adhesion effects of daikenchuto via endogenous adrenomedullin enhancement in Crohn's disease mouse model.
OBJECTIVE
Adrenomedullin (ADM) is a member of the calcitonin family of regulatory peptides, and is reported to have anti-inflammatory effects in animal models of Crohn's disease (CD). We investigated the therapeutic effects of daikenchuto (DKT), an extracted Japanese herbal medicine, on the regulation of endogenous ADM in the gastrointestinal tract in a CD mouse model.


METHODS
Colitis was induced in mice by intrarectal instillation of 2,4,6-trinitrobenzenesulfonic acid (TNBS); afterwards, DKT was given orally. Colonic damage was assessed on day 3 by macroscopic and microscopic observation, enzyme immunoassays of proinflammatory cytokines in the colonic mucosa, and serum amyloid A (SAA), a hepatic acute-phase protein. To determine the involvement of ADM, an ADM antagonist was instilled intrarectally before DKT administration. The effect of DKT on ADM production by intestinal epithelial cells was evaluated by enzyme immunoassay and real-time PCR.


RESULTS
DKT significantly attenuated mucosal damage and colonic inflammatory adhesions, and inhibited elevations of SAA in plasma and the proinflammatory cytokines TNFα and IFNγ in the colon. Small and large intestinal epithelial cells produced higher levels of ADM after DKT stimulation. A DKT-treated IEC-6 cell line also showed enhanced ADM production at protein and mRNA levels. Abolition of this effect by pretreatment with an ADM antagonist shows that DKT appears to exert its anti-colitis effect via up-regulation of endogenous ADM in the intestinal tract.


CONCLUSIONS
DKT exerts beneficial effects in a CD mouse model through endogenous release and production of ADM. Endogenous ADM may be a therapeutic target for CD.
Division of Gastroenterologic and General Surgery, Department of Surgery, Asahikawa Medical College, Hokkaido 078-8510, Japan. kono@asahikawa-med.ac.jp
Toru
T
Kono
Atsushi
A
Kaneko
Yoshiki
Y
Hira
Tatsuya
T
Suzuki
Naoyuki
N
Chisato
Nobuhiro
N
Ohtake
Naoko
N
Miura
Tsuyoshi
T
Watanabe
D053607:Adrenomedullin / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000627:therapeutic use*; D002448:Cell Adhesion; D002460:Cell Line; D003092:Colitis / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D003106:Colon / Q000473:pathology; D003424:Crohn Disease / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005434:Flow Cytometry; D015870:Gene Expression; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000378:metabolism; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D005894:Panax; D008517:Phytotherapy; D010936:Plant Extracts / Q000494:pharmacology* / Q000627:therapeutic use*; D051381:Rats; D000685:Serum Amyloid A Protein / Q000378:metabolism; D016896:Treatment Outcome; D014302:Trinitrobenzenesulfonic Acid; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation; D032106:Zanthoxylum; D030521:Zingiberaceae
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D010936:Plant Extracts; D000685:Serum Amyloid A Protein; D014409:Tumor Necrosis Factor-alpha; C121414:dai-kenchu-to; D053607:Adrenomedullin; D007371:Interferon-gamma; D014302:Trinitrobenzenesulfonic Acid