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

• DOI: 10.1016/j.bbrc.2007.06.065
• Publication Date: 2007-06-20T11:19:08Z
• Authors: Shin Maeda; Yohko Hikiba; Wataru Shibata; Tomoya Ohmae; Ayako Yanai; Keiji Ogura; Shingo Yamada; Masao Omata
• Keywords: Mice, Inbred C57BL; 0301 basic medicine; Mice; 03 medical and health sciences; Colonic Neoplasms; Biomarkers, Tumor; Animals; HMGB1 Protein; Colitis; Precancerous Conditions; Neoplasm Proteins; 3. Good health

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.