title: IL-4 abrogates T(H)17 cell-mediated inflammation by selective silencing of IL-23 in antigen-presenting cells.
abstract: Interleukin 4 (IL-4) can suppress delayed-type hypersensitivity reactions (DTHRs), including organ-specific autoimmune diseases in mice and humans. Despite the broadly documented antiinflammatory effect of IL-4, the underlying mode of action remains incompletely understood, as IL-4 also promotes IL-12 production by dendritic cells (DCs) and IFN-γ-producing T(H)1 cells in vivo. Studying the impact of IL-4 on the polarization of human and mouse DCs, we found that IL-4 exerts opposing effects on the production of either IL-12 or IL-23. While promoting IL-12-producing capacity of DCs, IL-4 completely abrogates IL-23. Bone marrow chimeras proved that IL-4-mediated suppression of DTHRs relies on the signal transducer and activator of transcription 6 (STAT6)-dependent abrogation of IL-23 in antigen-presenting cells. Moreover, IL-4 therapy attenuated DTHRs by STAT6- and activating transcription factor 3 (ATF3)-dependent suppression of the IL-23/T(H)17 responses despite simultaneous enhancement of IL-12/TH1 responses. As IL-4 therapy also improves psoriasis in humans and suppresses IL-23/T(H)17 responses without blocking IL-12/T(H)1, selective IL-4-mediated IL-23/T(H)17 silencing is promising as treatment against harmful inflammation, while sparing the IL-12-dependent T(H)1 responses.
authors: Department of Dermatology, Eberhard Karls University, 72076 Tübingen, Germany; Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; and Department of Dermatology, University Hospital of Zürich, 8091 Zürich, Switzerland; emmanuella.guenova@gmail.com mrocken@med.uni-tuebingen.de tilo.biedermann@tum.de.
authors: Emmanuella
authors: E
authors: Guenova
authors: Department of Dermatology, Eberhard Karls University, 72076 Tübingen, Germany;
authors: Yuliya
authors: Y
authors: Skabytska
authors: Department of Dermatology, Eberhard Karls University, 72076 Tübingen, Germany; Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; and Department of Dermatology, University Hospital of Zürich, 8091 Zürich, Switzerland;
authors: Wolfram
authors: W
authors: Hoetzenecker
authors: Department of Dermatology, Eberhard Karls University, 72076 Tübingen, Germany; Institute of Pharmacy, Department of Pharmacology and Toxicology, Freie Universität, 14195 Berlin, Germany;
authors: Günther
authors: http://orcid.org/0000-0002-4493-7597
authors: G
authors: Weindl
authors: Department of Dermatology, Eberhard Karls University, 72076 Tübingen, Germany;
authors: Karin
authors: K
authors: Sauer
authors: Department of Dermatology, Eberhard Karls University, 72076 Tübingen, Germany;
authors: Manuela
authors: M
authors: Tham
authors: NeuroVascular Coordination Research Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Republic of Korea;
authors: Kyu-Won
authors: KW
authors: Kim
authors: NeuroVascular Coordination Research Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Republic of Korea;
authors: Ji-Hyeon
authors: JH
authors: Park
authors: NeuroVascular Coordination Research Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Republic of Korea; Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 151-742, Republic of Korea;
authors: Ji Hae
authors: JH
authors: Seo
authors: Department of Dermatology, University Hospital of Zürich, 8091 Zürich, Switzerland;
authors: Desislava
authors: D
authors: Ignatova
authors: Department of Dermatology, University Hospital of Zürich, 8091 Zürich, Switzerland;
authors: Antonio
authors: A
authors: Cozzio
authors: Department of Dermatology, University Hospital of Zürich, 8091 Zürich, Switzerland;
authors: Mitchell P
authors: MP
authors: Levesque
authors: Department of Dermatology, Eberhard Karls University, 72076 Tübingen, Germany; Department of Dermatology and Allergy, Technische Universität München, Munich, Germany.
authors: Thomas
authors: T
authors: Volz
authors: Department of Dermatology, Eberhard Karls University, 72076 Tübingen, Germany; Department of Dermatology and Allergy, Technische Universität München, Munich, Germany.
authors: Martin
authors: M
authors: Köberle
authors: Department of Dermatology, Eberhard Karls University, 72076 Tübingen, Germany;
authors: Susanne
authors: S
authors: Kaesler
authors: Department of Dermatology and Allergology, Ludwig Maximilians University, 80337 Munich, Germany;
authors: Peter
authors: P
authors: Thomas
authors: Institute of Clinical Molecular Biology and Tumor Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, 81377 Munich, Germany;
authors: Reinhard
authors: R
authors: Mailhammer
authors: Department of Dermatology, Eberhard Karls University, 72076 Tübingen, Germany;
authors: Kamran
authors: K
authors: Ghoreschi
authors: Department of Dermatology, Heidelberg University Hospital, 69115 Heidelberg, Germany;
authors: Knut
authors: K
authors: Schäkel
authors: Institute of Statistics and Econometrics, Freie Universität, 14195 Berlin, Germany;
authors: Boyko
authors: B
authors: Amarov
authors: Department of Medical Biometry, Eberhard Karls University, 72076 Tübingen, Germany;
authors: Martin
authors: M
authors: Eichner
authors: Department of Dermatology, Eberhard Karls University, 72076 Tübingen, Germany;
authors: Martin
authors: M
authors: Schaller
authors: Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; and.
authors: Rachael A
authors: RA
authors: Clark
authors: Department of Dermatology, Eberhard Karls University, 72076 Tübingen, Germany; emmanuella.guenova@gmail.com mrocken@med.uni-tuebingen.de tilo.biedermann@tum.de.
authors: Martin
authors: M
authors: Röcken
authors: Department of Dermatology, Eberhard Karls University, 72076 Tübingen, Germany; Department of Dermatology and Allergy, Technische Universität München, Munich, Germany emmanuella.guenova@gmail.com mrocken@med.uni-tuebingen.de tilo.biedermann@tum.de.
authors: Tilo
authors: T
authors: Biedermann
mesh_terms: D000938:Antigen-Presenting Cells / Q000276:immunology*; D020868:Gene Silencing; D006801:Humans; D007249:Inflammation / Q000503:physiopathology*; D053759:Interleukin-23 / Q000235:genetics*; D015847:Interleukin-4 / Q000502:physiology*; D058504:Th17 Cells / Q000276:immunology*
chemical_list: D053759:Interleukin-23; D015847:Interleukin-4
keywords: IL-23; IL-4; TH17; dendritic cells; psoriasis
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