Hypoxia-inducible factor 1α induces corticosteroid-insensitive inflammation via reduction of histone deacetylase-2 transcription

C.E. Charron, P.-C. Chou, D.J.C. Coutts, V. Kumar, M. To, K. Akashi, L. Pinhu, M. Griffiths, I.M. Adcock, P.J. Barnes, K. Ito

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30 Citations (Scopus)

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% O2). Hypoxia enhanced interleukin-1β-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) 1a to a HIF response element at position 320, but not HIF-1b or HIF-2a, results in reduced polymerase II binding at the site, leading to reduced promoter activity ofHDAC2.Our results suggest that activation of HIF-1α by hypoxia decreases HDAC2 levels, resulting in amplified inflammation and corticosteroid resistance. © 2009 by The American Society for Biochemistry and Molecular Biology, Inc.
Original languageEnglish
Pages (from-to)36047-36054
Number of pages8
JournalJournal of Biological Chemistry
Volume284
Issue number52
DOIs
Publication statusPublished - Dec 25 2009

Keywords

  • A549 cells
  • Anti-inflammatory agents
  • Chronic inflammatory disease
  • Dexamethasones
  • Histone deacetylases
  • Hypoxia-inducible factor 1
  • Hypoxia-inducible factors
  • Hypoxic condition
  • Interleukin-1
  • Interleukin-8
  • Macrophage cells
  • Point mutations
  • Polymerase II
  • Promoter activities
  • Protein expressions
  • Response elements
  • Pathology
  • Transcription
  • Transcription factors
  • Drug products
  • corticosteroid
  • dexamethasone
  • DNA directed DNA polymerase alpha
  • histone deacetylase 2
  • hypoxia inducible factor 1alpha
  • hypoxia inducible factor 1beta
  • hypoxia inducible factor 2alpha
  • interleukin 8
  • messenger RNA
  • article
  • binding site
  • cell strain
  • controlled study
  • cytokine production
  • drug resistance
  • gene deletion
  • gene expression
  • gene function
  • human
  • human cell
  • hypoxia
  • inflammation
  • lung alveolus epithelium
  • macrophage
  • mutational analysis
  • point mutation
  • priority journal
  • promoter region
  • protein binding
  • protein degradation
  • protein expression
  • transcription initiation
  • transcription regulation
  • Basic Helix-Loop-Helix Transcription Factors
  • Cell Hypoxia
  • Dexamethasone
  • Drug Resistance
  • Gene Expression Regulation, Enzymologic
  • Glucocorticoids
  • Histone Deacetylase 2
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Inflammation
  • Interleukin-1beta
  • Macrophages
  • Point Mutation
  • Respiratory Mucosa
  • Response Elements
  • RNA, Messenger
  • U937 Cells

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    Charron, C. E., Chou, P-C., Coutts, D. J. C., Kumar, V., To, M., Akashi, K., Pinhu, L., Griffiths, M., Adcock, I. M., Barnes, P. J., & Ito, K. (2009). Hypoxia-inducible factor 1α induces corticosteroid-insensitive inflammation via reduction of histone deacetylase-2 transcription. Journal of Biological Chemistry, 284(52), 36047-36054. https://doi.org/10.1074/jbc.M109.025387