title: Oligosaccharides from agar inhibit murine intestinal inflammation through the induction of heme oxygenase-1 expression.
abstract: BACKGROUND
  Agarose is hydrolyzed easily to yield oligosaccharides, designated as agaro-oligosaccharides (AGOs). Recently, it has been demonstrated that AGOs induce heme oxygenase-1 (HO-1) expression in macrophages and that they might lead to anti-inflammatory property. Nevertheless, the molecular mechanism of AGO-mediated HO-1 induction remains unknown, as does AGOs' ability to elicit anti-inflammatory activity in vivo. This study was undertaken to uncover the mechanism of AGO-mediated HO-1 induction and to investigate the therapeutic effect of AGOs on intestinal inflammation.
  
  
  METHODS
  Mice were treated with 2,4,6-trinitrobenzene sulfonic acid (TNBS) to induce colitis. The respective degrees of mucosal injury of mice that had received AGO and control mice were compared. We investigated HO-1 expression using Western blotting, quantitative real-time PCR (qRT-PCR), and immunohistochemistry. The expression of tumor necrosis factor-α (TNF-α) was measured using qRT-PCR and enzyme-linked immunosorbent assay.
  
  
  RESULTS
  AGO administration induced HO-1 expression in colonic mucosa. The induction was observed mainly in F4/80 positive macrophages. Increased colonic damage and myeloperoxidase activity after TNBS treatment were inhibited by AGO administration. TNBS treatment induced TNF-α expression, and AGO administration suppressed induction. However, HO inhibitor canceled AGO-mediated amelioration of colitis. In RAW264 cells, AGOs enhanced HO-1 expression time-dependently and concentration-dependently and suppressed lipopolysaccharide-induced TNF-α expression. Furthermore, agarotetraose-mediated HO-1 induction required NF-E2-related factor 2 function and phosphorylation of c-jun N-terminal kinase.
  
  
  CONCLUSIONS
  We infer that AGO administration inhibits TNBS-induced colitis in mice through HO-1 induction in macrophages. Consequently, oral administration of AGOs might be an important therapeutic strategy for inflammatory bowel disease.
authors.affiliation: Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, Kyoto, 602-8566, Japan.
authors.forename: Yasuki
authors.initials: Y
authors.lastname: Higashimura
authors.forename: Yuji
authors.initials: Y
authors.lastname: Naito
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Takagi
authors.forename: Katsura
authors.initials: K
authors.lastname: Mizushima
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Hirai
authors.forename: Akihito
authors.initials: A
authors.lastname: Harusato
authors.forename: Hiromu
authors.initials: H
authors.lastname: Ohnogi
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Yamaji
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Inui
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Nakano
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Yoshikawa
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D015153:Blotting, Western; D002460:Cell Line; D003092:Colitis / Q000503:physiopathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation / Q000503:physiopathology / Q000517:prevention & control*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009844:Oligosaccharides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D012685:Sepharose / Q000378:metabolism; D013997:Time Factors; D014302:Trinitrobenzenesulfonic Acid / Q000633:toxicity
chemical_list: D000893:Anti-Inflammatory Agents; D009844:Oligosaccharides; D014302:Trinitrobenzenesulfonic Acid; D012685:Sepharose; D051547:Heme Oxygenase-1