Opposite functions of STAT3 and Smad3 in regulating Tiam1 expression in Th17 cells
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Taylor and Francis Inc.
Abstract
We recently showed that Tiam1 expression is induced in pro-inflammatory T helper 17 (Th17) cells differentiated with interleukin (IL)-6 and TGF-β1, and together with Rac1 promote Th17 cell development and autoimmunity in a mouse model of multiple sclerosis. Here we found that STAT3 and Smad3, downstream transcription factors of IL-6 and TGF-β1, respectively, play opposing roles in regulating Tiam1 transcription in CD4+ T-cells. While IL-6-STAT3 signaling promotes Tiam1 expression, TGF-β1-Smad3 induces the opposite outcome. At the Tiam1 promoter, both STAT3 and Smad3 bind to the Tiam1 promoter in Th17 cells. However, STAT3 induces Tiam1 promoter activity whereas Smad3 competes with STAT3 and inhibits its activity. Our findings uncover the complexity of STAT3/Smad3 signaling in regulating Tiam1 expression and Th17 cells. © 2017, © 2017 Taylor & Francis.
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Keywords
Smad3, Stat3, Th17, Tiam1, Animals, Autoimmunity, Gene expression regulation, Mice, Promoter regions, genetic, Signal transduction, Smad3 protein, Stat3 transcription factor, T-lymphoma invasion and metastasis-inducing protein 1, Th17 cells, Interleukin 6, Messenger rna, Rac1 protein, Stat3 protein, T lymphoma invasion and metastasis inducing protein 1, Transforming growth factor beta1, Animal cell, Animal model, Article, Binding site, Cd4+ t lymphocyte, Cell differentiation, Cell maturation, Cell stimulation, Chromatin immunoprecipitation polymerase chain reaction, Controlled study, Gene expression, Gene expression assay, Genetic transfection, Human, Human cell, Immunoprecipitation, Luciferase assay, Mouse, Multiple sclerosis, Nonhuman, Polarization, Promoter region, Protein expression, Real time polymerase chain reaction, Sequence analysis, Th17 cell, Western blotting, Animal, Cytology, Genetics, Immunology, Metabolism