{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T02:25:22Z","timestamp":1791944722098,"version":"4.3.4"},"reference-count":60,"publisher":"National Academy of Sciences","issue":"18","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2012,5]]},"abstract":"<jats:p>\n                    To address the role of Tpl2, a MAP3K8 that regulates innate\/adaptive immunity and inflammation, in intestinal tumorigenesis, we crossed a\n                    <jats:italic>Tpl2<\/jats:italic>\n                    KO allele into the\n                    <jats:italic>\n                      Apc\n                      <jats:sup>min\/+<\/jats:sup>\n                    <\/jats:italic>\n                    genetic background. Here, we show that Apc\n                    <jats:sup>min\/+<\/jats:sup>\n                    \/Tpl2\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    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,\n                    <jats:italic>Tpl2<\/jats:italic>\n                    ablation promoted intestinal inflammation. IL-10 levels and regulatory T-cell numbers were lower in the intestines of Tpl2\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    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\n                    <jats:italic>Tpl2<\/jats:italic>\n                    . 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\n                    <jats:sup>min\/+<\/jats:sup>\n                    \/Tpl2\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    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.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1115098109","type":"journal-article","created":{"date-parts":[[2012,3,27]],"date-time":"2012-03-27T00:28:13Z","timestamp":1332808093000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":49,"title":["<i>Tpl2<\/i>\n                    ablation promotes intestinal inflammation and tumorigenesis in\n                    <i>\n                      Apc\n                      <sup>min<\/sup>\n                    <\/i>\n                    mice by inhibiting IL-10 secretion and regulatory T-cell generation"],"prefix":"10.1073","volume":"109","author":[{"given":"Oksana B.","family":"Serebrennikova","sequence":"first","affiliation":[{"name":"Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA 02111;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christos","family":"Tsatsanis","sequence":"additional","affiliation":[{"name":"Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA 02111;"},{"name":"School of Medicine, University of Crete, Heraklion, 710 03 Crete, Greece;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changchuin","family":"Mao","sequence":"additional","affiliation":[{"name":"Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA 02111;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elias","family":"Gounaris","sequence":"additional","affiliation":[{"name":"Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenying","family":"Ren","sequence":"additional","affiliation":[{"name":"Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA 02111;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda D.","family":"Siracusa","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aristides G.","family":"Eliopoulos","sequence":"additional","affiliation":[{"name":"School of Medicine, University of Crete, Heraklion, 710 03 Crete, Greece;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khashayarsha","family":"Khazaie","sequence":"additional","affiliation":[{"name":"Robert H. 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