title: IL-1 signaling modulates activation of STAT transcription factors to antagonize retinoic acid signaling and control the TH17 cell-iTreg cell balance.
abstract: Interleukin 17 (IL-17)-producing helper T cells (TH17 cells) and CD4(+) inducible regulatory T cells (iTreg cells) emerge from an overlapping developmental program. In the intestines, the vitamin A metabolite retinoic acid (RA) is produced at steady state and acts as an important cofactor to induce iTreg cell development while potently inhibiting TH17 cell development. Here we found that IL-1 was needed to fully override RA-mediated expression of the transcription factor Foxp3 and induce protective TH17 cell responses. By repressing expression of the negative regulator SOCS3 dependent on the transcription factor NF-κB, IL-1 increased the amplitude and duration of phosphorylation of the transcription factor STAT3 induced by TH17-polarizing cytokines, which led to an altered balance in the binding of STAT3 and STAT5 to shared consensus sequences in developing T cells. Thus, IL-1 signaling modulated STAT activation downstream of cytokine receptors differently to control the TH17 cell-iTreg cell developmental fate.
authors: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors: Rajatava
authors: R
authors: Basu
authors: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors: Sarah K
authors: SK
authors: Whitley
authors: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors: Suniti
authors: S
authors: Bhaumik
authors: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors: Carlene L
authors: CL
authors: Zindl
authors: Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors: Trenton R
authors: TR
authors: Schoeb
authors: Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors: Etty N
authors: EN
authors: Benveniste
authors: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
authors: Warren S
authors: WS
authors: Pear
authors: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors: Robin D
authors: RD
authors: Hatton
authors: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors: Casey T
authors: CT
authors: Weaver
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*; D058504:Th17 Cells / Q000378:metabolism*; D014212:Tretinoin / Q000378:metabolism*
chemical_list: D007375:Interleukin-1; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; C491411:Socs3 protein, mouse; C494087:Stat3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014212:Tretinoin
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