title: Sensitivity and resistance to regulation by IL-4 during Th17 maturation.
abstract: Th17 cells are highly pathogenic in a variety of immune-mediated diseases, and a thorough understanding of the mechanisms of cytokine-mediated suppression of Th17 cells has great therapeutic potential. In this article, we characterize the regulation of both in vitro- and in vivo-derived Th17 cells by IL-4. We demonstrate that IL-4 suppresses reactivation of committed Th17 cells, even in the presence of TGF-β, IL-6, and IL-23. Downregulation of IL-17 by IL-4 is dependent on STAT6 and mediated by inhibition of STAT3 binding at the Il17a promoter. Although Th1 cytokines were shown to induce IFN-γ expression by Th17 cells, IL-4 does not induce a Th2 phenotype in Th17 cells. Suppression by IL-4 is stable and long-lived when applied to immature Th17 cells, but cells that have undergone multiple rounds of stimulation, either in vivo during a Th17-mediated inflammatory disease, or in vitro, become resistant to suppression by IL-4 and lose the ability to signal through IL-4R. Thus, although IL-4 is a potent suppressor of the Th17 genetic program at early stages after differentiation, prolonged stimulation renders Th17 cells impervious to regulatory cytokines.
authors.affiliation: Division of Rheumatology, Department of Internal Medicine and Rheumatic Disease Research Core Center, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Cooney
authors.forename: Keara
authors.initials: K
authors.lastname: Towery
authors.forename: Judith
authors.initials: J
authors.lastname: Endres
authors.forename: David A
authors.initials: DA
authors.lastname: Fox
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D050990:GATA3 Transcription Factor / Q000502:physiology; D006131:Growth Inhibitors / Q000037:antagonists & inhibitors / Q000502:physiology*; D016130:Immunophenotyping; D020381:Interleukin-17 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000502:physiology*; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000502:physiology; D058504:Th17 Cells / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism
chemical_list: D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D006131:Growth Inhibitors; D020381:Interleukin-17; D050796:STAT3 Transcription Factor; D050800:STAT6 Transcription Factor; C494087:Stat3 protein, mouse; C494100:Stat6 protein, mouse; D015847:Interleukin-4