TY - JOUR
T1 - Tpl2 ablation promotes intestinal inflammation and tumorigenesis in Apcmin mice by inhibiting IL-10 secretion and regulatory T-cell generation
AU - Serebrennikova, Oksana B.
AU - Tsatsanis, Christos
AU - Mao, Changchuin
AU - Gounaris, Elias
AU - Ren, Wenying
AU - Siracusa, Linda D.
AU - Eliopoulos, Aristides G.
AU - Khazaie, Khashayarsha
AU - Tsichlis, Philip N.
PY - 2012/5/1
Y1 - 2012/5/1
N2 - 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.
AB - 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.
KW - IL-6
KW - Inflammatory bowel disease
KW - TNF-α
KW - Th17 cells
KW - Tr1 cells
UR - http://www.scopus.com/inward/record.url?scp=84860804347&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84860804347&partnerID=8YFLogxK
U2 - 10.1073/pnas.1115098109
DO - 10.1073/pnas.1115098109
M3 - Article
C2 - 22451924
AN - SCOPUS:84860804347
SN - 0027-8424
VL - 109
SP - E1082-E1091
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 18
ER -