Tumor development in murine ulcerative colitis depends on MyD88 signaling of colonic F4/80+CD11bhighGr1low macrophages
Gabriela Schiechl, … , Warren Strober, Stefan Fichtner-Feigl
Gabriela Schiechl, … , Warren Strober, Stefan Fichtner-Feigl
Published April 25, 2011
Citation Information: J Clin Invest. 2011;121(5):1692-1708. https://doi.org/10.1172/JCI42540.
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Tumor development in murine ulcerative colitis depends on MyD88 signaling of colonic F4/80+CD11bhighGr1low macrophages

Abstract

Patients with prolonged ulcerative colitis (UC) frequently develop colorectal adenocarcinoma for reasons that are not fully clear. To analyze inflammation-associated colonic tumorigenesis, we developed a chronic form of oxazolone-induced colitis in mice that, similar to UC, was distinguished by the presence of IL-13–producing NKT cells. In this model, the induction of tumors using azoxymethane was accompanied by the coappearance of F4/80+CD11bhighGr1low M2 macrophages, cells that undergo polarization by IL-13 and are absent in tumors that lack high level IL-13 production. Importantly, this subset of macrophages was a source of tumor-promoting factors, including IL-6. Similar to dextran sodium sulfate–induced colitis, F4/80+CD11bhighGr1intermediate macrophages were present in the mouse model of chronic oxazolone-induced colitis and may influence tumor development through production of TGF-β1, a cytokine that inhibits tumor immunosurveillance. Finally, while robust chronic oxazolone-induced colitis developed in myeloid differentiation primary response gene 88–deficient (Myd88–/–) mice, these mice did not support tumor development. The inhibition of tumor development in Myd88–/– mice correlated with cessation of IL-6 and TGF-β1 production by M2 and F4/80+CD11bhighGr1intermediate macrophages, respectively, and was reversed by exogenous IL-6. These data show that an UC-like inflammation may facilitate tumor development by providing a milieu favoring development of MyD88-dependent tumor-supporting macrophages.

Authors

Gabriela Schiechl, Bernhard Bauer, Ivan Fuss, Sven A. Lang, Christian Moser, Petra Ruemmele, Stefan Rose-John, Markus F. Neurath, Edward K. Geissler, Hans-Jürgen Schlitt, Warren Strober, Stefan Fichtner-Feigl

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Figure 2

Cytokine expression and IL-6 dependency of AOM-induced tumors.

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Cytokine expression and IL-6 dependency of AOM-induced tumors. (A) Cytok...
(A) Cytokine expression during chronic oxa-colitis and chronic oxa-colitis with AOM-induced tumors. Cells were extracted from the lamina propria and stimulated for 48 hours. Cytokine concentrations were determined in culture supernatants by ELISA. Data shown are mean ± SEM from individual cultures of cells derived from mice in 2 separate experiments (n = 6 mice per group). *P ≤ 0.05. (B) Body weight after treatment with anti–IL-6 antibody. Data shown are mean ± SEM (n = 6 mice per group). (C) H&E staining of representative inflamed areas of colon sections (original magnification, ×10) and histology score on day 49 of oxa-colitis with AOM-induced tumors following treatment with anti–IL-6 antibody. Horizontal bars are mean values (n = 6 mice per group). Individual symbols represent 1 mouse. (D) IL-13 production on day 49 of oxa-colitis and oxa-colitis with AOM-induced tumors after treatment with anti–IL-6 antibody. Cells were extracted from the lamina propria on day 49. Cytokine concentrations were determined in culture supernatants by ELISA. Data shown are mean ± SEM from individual cultures of cells derived from mice in 2 separate experiments (n = 6 mice per group). *P ≤ 0.05. (E) Number of tumor nodules on day 49 of oxa-colitis with AOM-induced tumors after treatment with anti–IL-6 antibody. Horizontal bars are mean values (n = 6 mice per group). Individual symbols represent 1 mouse. *P ≤ 0.05.