Essential roles of high-mobility group box 1 in the development of murine colitis and colitis-associated cancer

• Published in: Biochemical and biophysical research communications Vol. 360; no. 2; pp. 394 - 400
• Main Authors: Maeda, Shin, Hikiba, Yohko, Shibata, Wataru, Ohmae, Tomoya, Yanai, Ayako, Ogura, Keiji, Yamada, Shingo, Omata, Masao
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 24-08-2007
• Subjects: 60 APPLIED LIFE SCIENCES; Animals; Biomarkers, Tumor - blood; Colitis - blood; Colitis - complications; Colonic Neoplasms - blood; Colonic Neoplasms - etiology; DEXTRAN; GENE REGULATION; High-mobility group box 1; HMGB1 Protein - blood; Inflammatory bowel disease; LARGE INTESTINE; LYMPHOKINES; MACROPHAGES; MICE; Mice, Inbred C57BL; MOBILITY; Neoplasm Proteins - blood; NEOPLASMS; NF-κB; Precancerous Conditions - blood; Proinflammatory cytokine; SALTS; SULFATES; Inflammatory bowel disease; NF-κB; DSS; Proinflammatory cytokine; High-mobility group box 1; IBD; HMGB1
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2007.06.065

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-κB 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-κB 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.