Activation of the IL-6/Stat3 via
IL-6 trans-signaling plays an important role in the pathogenesis of
inflammatory bowel disease.
Colitis-associated cancer (CAC) is a large bowel
cancer and occurs with long-standing
inflammatory bowel disease. The role of the IL-6/Stat3 in the development of CAC has not been fully understood. We investigate whether
IL-6 trans-signaling contributes to the development of CAC using a mouse
colitis-associated premalignant
cancer (CApC) model. Chronic
colitis (CC) was induced in BALB/c mice using
dextran sodium sulfate. CApC was induced by
dextran sodium sulfate treatment to CC-affected mice.
IL-6 expression was determined by quantitative RT-PCR and immunofluorescence staining in colon. Phospho-Stat3 expression was examined by Western blotting and immunofluorescence analysis. The expression of
IL-6 receptors (i.e., the IL-6R alpha-chain and gp130) and
tumor necrosis factor-alpha converting enzyme in the colon was examined by
laser-capture microdissection and immunofluorescence staining. Soluble IL-6R alpha (sIL-6R alpha) was examined by Western blotting of epithelial cell-depleted colonic tissues. We also investigated whether a soluble gp130-Fc fusion
protein could prevent CApC.
IL-6 expression was increased in the colon of CC- and CApC-affected mice and was restricted to lamina propria-macrophages. The expression of IL-6R alpha and
tumor necrosis factor-alpha converting enzyme was increased in the lamina propria CD11b-macrophages of CC-affected mice. sIL-6R alpha expression was also increased in these tissues. Reduced levels of IL-6R alpha generation were observed in the colonic epithelial cells of CC- and CApC-affected mice and were associated with the increased expression of gp130 and phospho-Stat3. Treatment with soluble gp130Fc significantly reduced the CApC.
IL-6 trans-signaling in epithelial cells induced by macrophage-derived IL-6/sIL-6R alpha plays a crucial role in the development of CAC.