Unknown

Dataset Information

0

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


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.

SUBMITTER: Serebrennikova OB 

PROVIDER: S-EPMC3344997 | biostudies-literature |

REPOSITORIES: biostudies-literature

Similar Datasets

| S-EPMC2851824 | biostudies-other
| S-EPMC5378314 | biostudies-literature
| S-EPMC3484449 | biostudies-literature
| S-EPMC4136553 | biostudies-literature
| S-EPMC4766010 | biostudies-literature
| S-EPMC3868878 | biostudies-other
2022-06-30 | E-MTAB-10470 | biostudies-arrayexpress
| S-EPMC3963510 | biostudies-other
| S-EPMC3778073 | biostudies-literature
| S-EPMC5922364 | biostudies-literature