Essential roles of IL-6 trans-signaling in colonic epithelial cells, induced by the IL-6/soluble-IL-6 receptor derived from lamina propria macrophages, on the development of colitis-associated premalignant cancer in a murine model.
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.
Matsumoto
Satoshi
S
Yakult Central Institute for Microbiological Research, Tokyo, Japan. satoshi-matsumoto@yakult.co.jp
Hara
Taeko
T
Mitsuyama
Keiichi
K
Yamamoto
Mayuko
M
Tsuruta
Osamu
O
Sata
Michio
M
Scheller
Jürgen
J
Rose-John
Stefan
S
Kado
Sho-ichi
S
Takada
Toshihiko
T
D000818:Animals; D002908:Chronic Disease; D003106:Colon / Q000166:cytology / Q000276:immunology*; D015179:Colorectal Neoplasms / Q000276:immunology / Q000473:pathology; D016264:Dextran Sulfate / Q000008:administration & dosage; D004195:Disease Models, Animal; D005260:Female; D018836:Inflammation Mediators / Q000008:administration & dosage; D015850:Interleukin-6 / Q000502:physiology*; D007413:Intestinal Mucosa / Q000276:immunology* / Q000473:pathology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009092:Mucous Membrane / Q000276:immunology / Q000473:pathology; D011230:Precancerous Conditions / Q000276:immunology* / Q000473:pathology; D019947:Receptors, Interleukin-6 / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology*
D018836:Inflammation Mediators; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D016264:Dextran Sulfate