Abstract
IL-22 has dual functions during tumorigenesis. Short term IL-22 production protects against genotoxic stress, whereas uncontrolled IL-22 activity promotes tumor growth; therefore, tight regulation of IL-22 is essential. TGF-β1 promotes the differentiation of Th17 cells, which are known to be a major source of IL-22, but the effect of TGF-β signaling on the production of IL-22 in CD4+ T cells is controversial. Here we show an increased presence of IL-17+IL-22+ cells and TGF-β1 in colorectal cancer compared to normal adjacent tissue, whereas the frequency of IL-22 single producing cells is not changed. Accordingly, TGF-β signaling in CD4+ T cells (specifically Th17 cells) promotes the emergence of IL-22-producing Th17 cells and thereby tumorigenesis in mice. IL-22 single producing T cells, however, are not dependent on TGF-β signaling. We show that TGF-β, via AhR induction, and PI3K signaling promotes IL-22 production in Th17 cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Basic Helix-Loop-Helix Transcription Factors / metabolism
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Carcinogenesis / immunology
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Cell Differentiation
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Colitis / complications*
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Colitis / immunology
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Colonic Neoplasms / etiology*
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Colonic Neoplasms / immunology
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Colonic Neoplasms / pathology
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Colorectal Neoplasms / etiology
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Colorectal Neoplasms / immunology
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Colorectal Neoplasms / pathology
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Disease Models, Animal
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Female
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Humans
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Interleukin-17 / genetics
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Interleukin-17 / metabolism
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Interleukin-22
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Interleukins / biosynthesis*
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Lymphocytes, Tumor-Infiltrating / immunology
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Lymphocytes, Tumor-Infiltrating / pathology
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Phosphatidylinositol 3-Kinases / metabolism
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Receptors, Aryl Hydrocarbon / genetics
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Receptors, Aryl Hydrocarbon / metabolism
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Signal Transduction / immunology
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Th17 Cells / immunology*
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Th17 Cells / pathology
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Transforming Growth Factor beta / metabolism*
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Transforming Growth Factor beta1 / metabolism
Substances
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Ahr protein, mouse
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Basic Helix-Loop-Helix Transcription Factors
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Il17a protein, mouse
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Interleukin-17
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Interleukins
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Receptors, Aryl Hydrocarbon
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TGFB1 protein, human
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Transforming Growth Factor beta
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Transforming Growth Factor beta1