title: Interleukin-4 and interferon-γ orchestrate an epithelial polarization in the airways.
abstract: Interferon-γ (IFN-γ) and interleukin-4 (IL-4) are key effector cytokines for the differentiation of T helper type 1 and 2 (Th1 and Th2) cells. Both cytokines induce fate-decisive transcription factors such as GATA3 and TBX21 that antagonize the polarized development of opposite phenotypes by direct regulation of each other's expression along with many other target genes. Although it is well established that mesenchymal cells directly respond to Th1 and Th2 cytokines, the nature of antagonistic differentiation programs in airway epithelial cells is only partially understood. In this study, primary normal human bronchial epithelial cells (NHBEs) were exposed to IL-4, IFN-γ, or both and genome-wide transcriptome analysis was performed. The study uncovers an antagonistic regulation pattern of IL-4 and IFN-γ in NHBEs, translating the Th1/Th2 antagonism directly in epithelial gene regulation. IL-4- and IFN-γ-induced transcription factor hubs form clusters, present in antagonistically and polarized gene regulation networks. Furthermore, the IL-4-dependent induction of IL-24 observed in rhinitis patients was downregulated by IFN-γ, and therefore IL-24 represents a potential biomarker of allergic inflammation and a Th2 polarized condition of the epithelium.
authors.affiliation: Center of Allergy & Environment (ZAUM), Technical University of Munich and Helmholtz Center Munich, German Research Center for Environmental Health, Germany, Member of the German Center for Lung Research (DZL), Munich, Germany.
authors.forename: U M
authors.initials: UM
authors.lastname: Zissler
authors.affiliation: Center of Allergy & Environment (ZAUM), Technical University of Munich and Helmholtz Center Munich, German Research Center for Environmental Health, Germany, Member of the German Center for Lung Research (DZL), Munich, Germany.|Department of Otorhinolaryngology and Head and Neck Surgery, Medical School, Technical University of Munich, Munich, Germany.
authors.forename: A M
authors.initials: AM
authors.lastname: Chaker
authors.affiliation: Center of Allergy & Environment (ZAUM), Technical University of Munich and Helmholtz Center Munich, German Research Center for Environmental Health, Germany, Member of the German Center for Lung Research (DZL), Munich, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Effner
authors.affiliation: Center of Allergy & Environment (ZAUM), Technical University of Munich and Helmholtz Center Munich, German Research Center for Environmental Health, Germany, Member of the German Center for Lung Research (DZL), Munich, Germany.|Department of Otorhinolaryngology and Head and Neck Surgery, Medical School, Technical University of Munich, Munich, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Ulrich
authors.affiliation: Center of Allergy & Environment (ZAUM), Technical University of Munich and Helmholtz Center Munich, German Research Center for Environmental Health, Germany, Member of the German Center for Lung Research (DZL), Munich, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Guerth
authors.affiliation: Department of Otorhinolaryngology and Head and Neck Surgery, Medical School, Technical University of Munich, Munich, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Piontek
authors.affiliation: Center of Allergy & Environment (ZAUM), Technical University of Munich and Helmholtz Center Munich, German Research Center for Environmental Health, Germany, Member of the German Center for Lung Research (DZL), Munich, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Dietz
authors.affiliation: Institute of Pharmacology and Toxicology, Medical School, Technical University of Munich, Munich, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Regn
authors.affiliation: Institute of Computational Biology, Technical University of Munich and Helmholtz Center Munich, German Research Center for Environmental Health, Munich, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Knapp
authors.affiliation: Institute of Computational Biology, Technical University of Munich and Helmholtz Center Munich, German Research Center for Environmental Health, Munich, Germany.|Department of Mathematics, Technical University of Munich, Garching, Germany.
authors.forename: F J
authors.initials: FJ
authors.lastname: Theis
authors.affiliation: Division of Innate Immunity, Research Center Borstel, Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Borstel, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Heine
authors.affiliation: Center of Allergy & Environment (ZAUM), Technical University of Munich and Helmholtz Center Munich, German Research Center for Environmental Health, Germany, Member of the German Center for Lung Research (DZL), Munich, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Suttner
authors.affiliation: Center of Allergy & Environment (ZAUM), Technical University of Munich and Helmholtz Center Munich, German Research Center for Environmental Health, Germany, Member of the German Center for Lung Research (DZL), Munich, Germany.
authors.forename: C B
authors.initials: CB
authors.lastname: Schmidt-Weber
mesh_terms: D000328:Adult; D001980:Bronchi / Q000473:pathology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000276:immunology; D053263:Gene Regulatory Networks; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology*; D015847:Interleukin-4 / Q000276:immunology*; D007378:Interleukins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D061251:Primary Cell Culture; D020545:Respiratory Mucosa / Q000473:pathology / Q000502:physiology*; D065631:Rhinitis, Allergic / Q000175:diagnosis / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology*; D055815:Young Adult; D000099180:Interleukin-24
chemical_list: D007371:Interferon-gamma; D015847:Interleukin-4; D007378:Interleukins; D000099180:Interleukin-24