Tpl2ablation promotes intestinal inflammation and tumorigenesis inApcminmice by inhibiting IL-10 secretion and regulatory T-cell generation
- 26 March 2012
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 109 (18), E1082-E1091
- https://doi.org/10.1073/pnas.1115098109
Abstract
To address the role of Tpl2, a MAP3K8 that regulates innate/adaptive immunity and inflammation, in intestinal tumorigenesis, we crossed a Tpl2 KO allele into the Apcmin/+ genetic background. Here, we show that Apcmin/+/Tpl2−/− mice exhibit a fivefold increase in the number of intestinal adenomas. Bone marrow transplantation experiments revealed that the enhancement of polyposis was partially hematopoietic cell-driven. Consistent with this observation, Tpl2 ablation promoted intestinal inflammation. IL-10 levels and regulatory T-cell numbers were lower in the intestines of Tpl2−/− mice, independent of Apc and polyp status, suggesting that they were responsible for the initiation of the enhancement of tumorigenesis caused by the ablation of Tpl2. The low IL-10 levels correlated with defects in mTOR activation and Stat3 phosphorylation in Toll-like receptor-stimulated macrophages and with a defect in inducible regulatory T-cell generation and function. Both polyp numbers and inflammation increased progressively with time. The rate of increase of both, however, was more rapid in Apcmin/+/Tpl2−/− mice, suggesting that the positive feedback initiated by inflammatory signals originating in developing polyps is more robust in these mice. This may be because these mice have a higher intestinal polyp burden as a result of the enhancement of tumor initiation.Keywords
This publication has 55 references indexed in Scilit:
- Loss of Single Immunoglobulin Interlukin-1 Receptor-Related Molecule Leads to Enhanced Colonic Polyposis in Apcmin MiceGastroenterology, 2010
- Regulatory T-cell stability and plasticity in mucosal and systemic immune systemsMucosal Immunology, 2010
- ERK activation drives intestinal tumorigenesis in Apcmin/+ miceNature Medicine, 2010
- Interleukin 10 acts on regulatory T cells to maintain expression of the transcription factor Foxp3 and suppressive function in mice with colitisNature Immunology, 2009
- Innate immune signaling by Toll-like receptor-4 (TLR4) shapes the inflammatory microenvironment in colitis-associated tumorsInflammatory Bowel Diseases, 2009
- Immunoregulatory functions of mTOR inhibitionNature Reviews Immunology, 2009
- Natural and Adaptive Foxp3+ Regulatory T Cells: More of the Same or a Division of Labor?Immunity, 2009
- Myeloid-derived suppressor cells as regulators of the immune systemNature Reviews Immunology, 2009
- Tpl2 and ERK transduce antiproliferative T cell receptor signals and inhibit transformation of chronically stimulated T cellsProceedings of the National Academy of Sciences of the United States of America, 2008
- Mast cells are an essential hematopoietic component for polyp developmentProceedings of the National Academy of Sciences of the United States of America, 2007