Prevention of colitic cancer by IL-6 trans-signaling inhibitors

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Colitic cancer is a large bowel cancer that occurs in a long-standing inflammatory bowel disease. The role of the IL-6/STAT3 pathway in the development of colitic cancer has not been fully understood. This study was conducted to investigate whether IL-6 trans-signaling contributes to the development of colitic cancer. Chronic colitis was induced by dextran sodium sulfate (DSS) to BALB/c mice. Colitic cancer was induced by additional DSS treatment to colitis-affected mice. IL-6 expression increased in the colon of colitis- and colitic cancer-affected mice, and this expression was restricted to lamina propria-macrophages. Both IL-6R and TACE expressions increased in macrophages in colitis tissue, and soluble IL6R was increased in these tissues. In contrast, IL-6R generation was reduced in the colonic epithelial cells in colitis- and colitic cancer-mice and was associated with increased expression of gp130 and phospho-STAT3. It should be noted that pre-treatment of soluble gp130Fc significantly reduced the tumorigenesis in the colon. IL-6 trans-signaling in epithelial cells, induced by macrophage-derived IL-6/soluble IL-6R, plays a crucial role in the development of colitic cancer. Soluble gp130Fc may be effective for the prevention of colitic cancer.