title: 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.
authors.affiliation: Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA 02111, USA.
authors.forename: Oksana B
authors.initials: OB
authors.lastname: Serebrennikova
authors.forename: Christos
authors.initials: C
authors.lastname: Tsatsanis
authors.forename: Changchuin
authors.initials: C
authors.lastname: Mao
authors.forename: Elias
authors.initials: E
authors.lastname: Gounaris
authors.forename: Wenying
authors.initials: W
authors.lastname: Ren
authors.forename: Linda D
authors.initials: LD
authors.lastname: Siracusa
authors.forename: Aristides G
authors.initials: AG
authors.lastname: Eliopoulos
authors.forename: Khashayarsha
authors.initials: K
authors.lastname: Khazaie
authors.forename: Philip N
authors.initials: PN
authors.lastname: Tsichlis
mesh_terms: D000236:Adenoma / Q000209:etiology / Q000235:genetics / Q000276:immunology; D000818:Animals; D016026:Bone Marrow Transplantation; D005260:Female; D015870:Gene Expression; D017491:Genes, APC; D015212:Inflammatory Bowel Diseases / Q000209:etiology* / Q000235:genetics / Q000276:immunology; D016753:Interleukin-10 / Q000096:biosynthesis*; D007413:Intestinal Mucosa / Q000276:immunology; D007414:Intestinal Neoplasms / Q000209:etiology* / Q000235:genetics / Q000276:immunology; D020930:MAP Kinase Kinase Kinases / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D018448:Models, Immunological; D011518:Proto-Oncogene Proteins / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: C556062:IL10 protein, mouse; D011518:Proto-Oncogene Proteins; D016753:Interleukin-10; D020930:MAP Kinase Kinase Kinases; C489843:Map3k8 protein, mouse