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

Oksana B. Serebrennikova, Christos Tsatsanis, Changchuin Mao, Elias Gounaris, Wenying Ren, Linda D. Siracusa, Aristides G. Eliopoulos, Khashayarsha Khazaie, Philip N. Tsichlis*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

41 Scopus citations


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 marrowtransplantation 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 tumori-genesis 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.

Original languageEnglish (US)
Pages (from-to)E1082-E1091
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number18
StatePublished - May 1 2012


  • IL-6
  • Inflammatory bowel disease
  • TNF-α
  • Th17 cells
  • Tr1 cells

ASJC Scopus subject areas

  • General


Dive into the research topics of 'Tpl2 ablation promotes intestinal inflammation and tumorigenesis in Apc<sup>min</sup> mice by inhibiting IL-10 secretion and regulatory T-cell generation'. Together they form a unique fingerprint.

Cite this