title: Tumor development in murine ulcerative colitis depends on MyD88 signaling of colonic F4/80+CD11b(high)Gr1(low) 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+CD11b(high)Gr1(low) 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+CD11b(high)Gr1(intermediate) 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+CD11b(high)Gr1(intermediate) 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.affiliation: Department of Surgery, University of Regensburg, Regensburg, Germany.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Schiechl
authors.forename: Bernhard
authors.initials: B
authors.lastname: Bauer
authors.forename: Ivan
authors.initials: I
authors.lastname: Fuss
authors.forename: Sven A
authors.initials: SA
authors.lastname: Lang
authors.forename: Christian
authors.initials: C
authors.lastname: Moser
authors.forename: Petra
authors.initials: P
authors.lastname: Ruemmele
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
authors.forename: Markus F
authors.initials: MF
authors.lastname: Neurath
authors.forename: Edward K
authors.initials: EK
authors.lastname: Geissler
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Schlitt
authors.forename: Warren
authors.initials: W
authors.lastname: Strober
authors.forename: Stefan
authors.initials: S
authors.lastname: Fichtner-Feigl
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D039481:CD11b Antigen / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003092:Colitis / Q000139:chemically induced; D003093:Colitis, Ulcerative / Q000378:metabolism*; D007249:Inflammation; D018793:Interleukin-13 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D010081:Oxazolone / Q000494:pharmacology; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D000950:Antigens, Ly; D039481:CD11b Antigen; D018793:Interleukin-13; D015850:Interleukin-6; C480309:Ly6G antigen, mouse; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D053773:Transforming Growth Factor beta1; D010081:Oxazolone