Schiechl, Gabriela and Bauer, Bernhard and Fuss, Ivan and Lang, Sven A. and Moser, Christian and Ruemmele, Petra and Rose-John, Stefan and Neurath, Markus F. and Geissler, Edward K. and Schlitt, Hans-Juergen and Strober, Warren and Fichtner-Feigl, Stefan (2011) Tumor development in murine ulcerative colitis depends on MyD88 signaling of colonic F4/80(+)CD11b(high)Gr1(low) macrophages. JOURNAL OF CLINICAL INVESTIGATION, 121 (5). pp. 1692-1708. ISSN 0021-9738,
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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 azotrymetharte 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-beta 1, 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-beta 1 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | INFLAMMATORY-BOWEL-DISEASE; NF-KAPPA-B; NK-T-CELLS; COLORECTAL-CANCER; OXAZOLONE COLITIS; SUPPRESSOR-CELLS; EPITHELIAL-CELLS; MICE; ACTIVATION; MODEL; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Chirurgie Medicine > Lehrstuhl für Pathologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 18 Jun 2020 13:34 |
| Last Modified: | 18 Jun 2020 13:34 |
| URI: | https://pred.uni-regensburg.de/id/eprint/20879 |
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