title: Essential roles of high-mobility group box 1 in the development of murine colitis and colitis-associated cancer.
abstract: High-mobility group box 1 (HMGB1) is a nuclear factor released extracellularly as a proinflammatory cytokine. We measured the HMGB1 concentration in the sera of mice with chemically induced colitis (DSS; dextran sulfate sodium salt) and found a marked increase. Inhibition of HMGB1 by neutralizing anti-HMGB1 antibody resulted in reduced inflammation in DSS-treated colons. In macrophages, HMGB1 induces several proinflammatory cytokines, such as IL-6, which are regulated by NF-kappaB activation. Two putative sources of HMGB1 were explored: in one, bacterial factors induce HMGB1 secretion from macrophages and in the other, necrotic epithelial cells directly release HMGB1. LPS induced a small amount of HMGB1 in macrophages, but macrophages incubated with supernatant prepared from necrotic cells and containing large amounts of HMGB1 activated NF-kappaB and induced IL-6. Using the colitis-associated cancer model, we demonstrated that neutralizing anti-HMGB1 antibody decreases tumor incidence and size. These observations suggest that HMGB1 is a potentially useful target for IBD treatment and the prevention of colitis-associated cancer.
authors.affiliation: Division of Gastroenterology, Institute for Adult Diseases, Asahi Life Foundation, 1-6-1 Marunouchi, Chiyoda-ku, Tokyo 100-0005, Japan. shinmaeda2-gi@umin.ac.jp
authors.forename: Shin
authors.initials: S
authors.lastname: Maeda
authors.forename: Yohko
authors.initials: Y
authors.lastname: Hikiba
authors.forename: Wataru
authors.initials: W
authors.lastname: Shibata
authors.forename: Tomoya
authors.initials: T
authors.lastname: Ohmae
authors.forename: Ayako
authors.initials: A
authors.lastname: Yanai
authors.forename: Keiji
authors.initials: K
authors.lastname: Ogura
authors.forename: Shingo
authors.initials: S
authors.lastname: Yamada
authors.forename: Masao
authors.initials: M
authors.lastname: Omata
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000097:blood*; D003092:Colitis / Q000097:blood* / Q000150:complications; D003110:Colonic Neoplasms / Q000097:blood* / Q000209:etiology; D024243:HMGB1 Protein / Q000097:blood*; D051379:Mice; D008810:Mice, Inbred C57BL; D009363:Neoplasm Proteins / Q000097:blood*; D011230:Precancerous Conditions / Q000097:blood*
chemical_list: D014408:Biomarkers, Tumor; D024243:HMGB1 Protein; D009363:Neoplasm Proteins