Hypoxia-inducible factor 1alpha induces corticosteroid-insensitive inflammation via reduction of histone deacetylase-2 transcription.
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.
Charron
Catherine E
CE
Section of Airway Disease, National Heart and Lung Institute, Imperial College London, London SW3 6LY, United Kingdom. Electronic address: c.charron@imperial.ac.uk.
Chou
Pai-Chien
PC
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.
Coutts
David J C
DJC
Section of Airway Disease, National Heart and Lung Institute, Imperial College London, London SW3 6LY, United Kingdom.
Kumar
Vaibhav
V
Section of Airway Disease, National Heart and Lung Institute, Imperial College London, London SW3 6LY, United Kingdom.
To
Masako
M
Section of Airway Disease, National Heart and Lung Institute, Imperial College London, London SW3 6LY, United Kingdom.
Akashi
Kenichi
K
Section of Airway Disease, National Heart and Lung Institute, Imperial College London, London SW3 6LY, United Kingdom.
Pinhu
Liao
L
Unit of Critical Care, Imperial College Royal Brompton Hospital Campus, London SW3 6NP, United Kingdom.
Griffiths
Mark
M
Unit of Critical Care, Imperial College Royal Brompton Hospital Campus, London SW3 6NP, United Kingdom.
Adcock
Ian M
IM
Section of Airway Disease, National Heart and Lung Institute, Imperial College London, London SW3 6LY, United Kingdom.
Barnes
Peter J
PJ
Section of Airway Disease, National Heart and Lung Institute, Imperial College London, London SW3 6LY, United Kingdom.
Ito
Kazuhiro
K
Section of Airway Disease, National Heart and Lung Institute, Imperial College London, London SW3 6LY, United Kingdom.
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
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