Tpl2 ablation promotes intestinal inflammation and tumorigenesis in Apcmin mice by inhibiting IL-10 secretion and regulatory T-cell generation

Proc Natl Acad Sci U S A. 2012 May 1;109(18):E1082-91. doi: 10.1073/pnas.1115098109. Epub 2012 Mar 26.

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 Apc(min/+) genetic background. Here, we show that Apc(min/+)/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 Apc(min/+)/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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoma / etiology
  • Adenoma / genetics
  • Adenoma / immunology
  • Animals
  • Bone Marrow Transplantation
  • Female
  • Gene Expression
  • Genes, APC*
  • Inflammatory Bowel Diseases / etiology*
  • Inflammatory Bowel Diseases / genetics
  • Inflammatory Bowel Diseases / immunology
  • Interleukin-10 / biosynthesis*
  • Intestinal Mucosa / immunology
  • Intestinal Neoplasms / etiology*
  • Intestinal Neoplasms / genetics
  • Intestinal Neoplasms / immunology
  • MAP Kinase Kinase Kinases / deficiency*
  • MAP Kinase Kinase Kinases / genetics
  • MAP Kinase Kinase Kinases / immunology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Mutant Strains
  • Models, Immunological
  • Proto-Oncogene Proteins / deficiency*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / immunology
  • T-Lymphocytes, Regulatory / immunology*

Substances

  • IL10 protein, mouse
  • Proto-Oncogene Proteins
  • Interleukin-10
  • MAP Kinase Kinase Kinases
  • Map3k8 protein, mouse