title: Human Th2 but not Th9 cells release IL-31 in a STAT6/NF-κB-dependent way.
abstract: IL-31, a member of the IL-6 protein family, is one of the latest additions to the list of T cell-derived cytokines. Th2 cells are regarded as a main source of IL-31, which is produced in response to stimulation by IL-4. Because the development of Th9 cells also requires IL-4 as a polarizing cytokine, the current study investigates IL-31 production in human Th9 cells compared with Th2 cells. We found that, although Th9 cells were able to release IL-31 during the first weeks of in vitro polarization, no IL-31 was detected in Th9 cultures after a final restimulation in the absence of polarizing cytokines. We further show that TGF-β, which is required to obtain Th9 cells in vitro, potently inhibits the release of IL-31 from Th2 cells, whereas IL-33, a cytokine associated with Th2-mediated inflammation, synergizes with IL-4 in inducing IL-31 secretion. To analyze the molecular mechanisms underlying the induction of IL-31, EMSAs, reporter gene assays, and small interfering RNA-based silencing experiments were carried out. We show that STAT6 and NF-κB are central players in mediating IL-31 expression induced by IL-4/IL-33. In addition, we identified a novel NF-κB-binding element within the Il31 promoter that mediates the enhancing effects of IL-33 on IL-4/STAT6-induced IL-31 expression in human Th2 cells. Taken together, this study shows that IL-4 is essential for the production of IL-31, whereas TGF-β significantly suppresses IL-31 expression at the mRNA and protein levels. As a consequence, in vitro polarized Th2 cells, but not Th9 cells, are able to release IL-31.
authors.affiliation: Department of Molecular Biology, University of Salzburg, 5020 Salzburg, Austria; and.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Maier
authors.affiliation: Department of Molecular Biology, University of Salzburg, 5020 Salzburg, Austria; and Department of Pathophysiology and Allergy Research, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Werner
authors.affiliation: Department of Molecular Biology, University of Salzburg, 5020 Salzburg, Austria; and.
authors.forename: Albert
authors.initials: A
authors.lastname: Duschl
authors.affiliation: Department of Pathophysiology and Allergy Research, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Barbara
authors.initials: B
authors.lastname: Bohle
authors.affiliation: Department of Molecular Biology, University of Salzburg, 5020 Salzburg, Austria; and jutta.horejs_hoeck@sbg.ac.at.
authors.forename: Jutta
authors.initials: J
authors.lastname: Horejs-Hoeck
mesh_terms: D001665:Binding Sites / Q000235:genetics; D015153:Blotting, Western; D002478:Cells, Cultured; D004357:Drug Synergism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D000067596:Interleukin-33; D007378:Interleukins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D006377:T-Lymphocytes, Helper-Inducer / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000494:pharmacology
chemical_list: C502187:IL31 protein, human; C506536:IL33 protein, human; D000067596:Interleukin-33; D007378:Interleukins; D016328:NF-kappa B; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D016212:Transforming Growth Factor beta