Essential roles of high-mobility group box 1 in the development of murine colitis and colitis-associated cancer.
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.
Maeda
Shin
S
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
Hikiba
Yohko
Y
Shibata
Wataru
W
Ohmae
Tomoya
T
Yanai
Ayako
A
Ogura
Keiji
K
Yamada
Shingo
S
Omata
Masao
M
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*
D014408:Biomarkers, Tumor; D024243:HMGB1 Protein; D009363:Neoplasm Proteins