Maeda Shin, Hikiba Yohko, Shibata Wataru, Ohmae Tomoya, Yanai Ayako, Ogura Keiji, Yamada Shingo, Omata Masao
Division of Gastroenterology, Institute for Adult Diseases, Asahi Life Foundation, 1-6-1 Marunouchi, Chiyoda-ku, Tokyo 100-0005, Japan.
Biochem Biophys Res Commun. 2007 Aug 24;360(2):394-400. doi: 10.1016/j.bbrc.2007.06.065. Epub 2007 Jun 19.
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.
高迁移率族蛋白B1（HMGB1）是一种作为促炎细胞因子在细胞外释放的核因子。我们测量了化学诱导性结肠炎（葡聚糖硫酸钠，DSS）小鼠血清中的HMGB1浓度，发现其显著升高。用抗HMGB1中和抗体抑制HMGB1可减轻DSS处理的结肠中的炎症。在巨噬细胞中，HMGB1诱导多种促炎细胞因子，如IL-6，这些细胞因子受NF-κB激活调节。我们探究了HMGB1的两个可能来源：其一，细菌因子诱导巨噬细胞分泌HMGB1；其二，坏死的上皮细胞直接释放HMGB1。脂多糖（LPS）在巨噬细胞中诱导少量HMGB1，但与含有大量HMGB1的坏死细胞制备的上清液孵育的巨噬细胞可激活NF-κB并诱导IL-6。使用结肠炎相关癌症模型，我们证明抗HMGB1中和抗体可降低肿瘤发生率和肿瘤大小。这些观察结果表明，HMGB1是炎症性肠病治疗和预防结肠炎相关癌症的一个潜在有用靶点。
