title: Hypoxia-inducible factor 1alpha induces corticosteroid-insensitive inflammation via reduction of histone deacetylase-2 transcription.
abstract: Corticosteroids are potent anti-inflammatory agents, but corticosteroid insensitivity is a major barrier for the treatment of some chronic inflammatory diseases. Here, we show that hypoxia induces corticosteroid-insensitive inflammation via reduced transcription of histone deacetylase-2 (HDAC2) in lung epithelial and macrophage cells. HDAC2 mRNA and protein expression was reduced under hypoxic conditions (1% O(2)). Hypoxia enhanced interleukin-1beta-induced interleukin-8 (CXCL8) production in A549 cells and decreased the ability of dexamethasone to suppress the CXCL8 production. Deletion or point mutation studies revealed that binding of the transcription factor hypoxia-inducible factor (HIF) 1alpha to a HIF response element at position -320, but not HIF-1beta or HIF-2alpha, results in reduced polymerase II binding at the site, leading to reduced promoter activity of HDAC2. Our results suggest that activation of HIF-1alpha by hypoxia decreases HDAC2 levels, resulting in amplified inflammation and corticosteroid resistance.
authors.affiliation: Section of Airway Disease, National Heart and Lung Institute, Imperial College London, London SW3 6LY, United Kingdom. Electronic address: c.charron@imperial.ac.uk.
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Charron
authors.affiliation: Section of Airway Disease, National Heart and Lung Institute, Imperial College London, London SW3 6LY, United Kingdom; Department of Thoracic Medicine, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei 10507, Taiwan.
authors.forename: Pai-Chien
authors.initials: PC
authors.lastname: Chou
authors.affiliation: Section of Airway Disease, National Heart and Lung Institute, Imperial College London, London SW3 6LY, United Kingdom.
authors.forename: David J C
authors.initials: DJC
authors.lastname: Coutts
authors.affiliation: Section of Airway Disease, National Heart and Lung Institute, Imperial College London, London SW3 6LY, United Kingdom.
authors.forename: Vaibhav
authors.initials: V
authors.lastname: Kumar
authors.affiliation: Section of Airway Disease, National Heart and Lung Institute, Imperial College London, London SW3 6LY, United Kingdom.
authors.forename: Masako
authors.initials: M
authors.lastname: To
authors.affiliation: Section of Airway Disease, National Heart and Lung Institute, Imperial College London, London SW3 6LY, United Kingdom.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Akashi
authors.affiliation: Unit of Critical Care, Imperial College Royal Brompton Hospital Campus, London SW3 6NP, United Kingdom.
authors.forename: Liao
authors.initials: L
authors.lastname: Pinhu
authors.affiliation: Unit of Critical Care, Imperial College Royal Brompton Hospital Campus, London SW3 6NP, United Kingdom.
authors.forename: Mark
authors.initials: M
authors.lastname: Griffiths
authors.affiliation: Section of Airway Disease, National Heart and Lung Institute, Imperial College London, London SW3 6LY, United Kingdom.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Adcock
authors.affiliation: Section of Airway Disease, National Heart and Lung Institute, Imperial College London, London SW3 6LY, United Kingdom.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Barnes
authors.affiliation: Section of Airway Disease, National Heart and Lung Institute, Imperial College London, London SW3 6LY, United Kingdom.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Ito
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D015687:Cell Hypoxia / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology*; D004351:Drug Resistance / Q000187:drug effects / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D005938:Glucocorticoids / Q000494:pharmacology*; D056464:Histone Deacetylase 2 / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000096:biosynthesis / Q000235:genetics; D008264:Macrophages / Q000378:metabolism; D017354:Point Mutation; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020545:Respiratory Mucosa / Q000378:metabolism; D020218:Response Elements / Q000235:genetics; D020298:U937 Cells; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D003907:Dexamethasone; D005938:Glucocorticoids; D056464:Histone Deacetylase 2; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D053583:Interleukin-1beta; D016209:Interleukin-8; D012333:RNA, Messenger; D000099162:Endothelial PAS Domain-Containing Protein 1; C508606:CXCL8 protein, human; C497442:HIF1A protein, human; C533423:HDAC2 protein, human