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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38 引文 斯高帕斯(Scopus)

摘要

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.
原文英語
頁(從 - 到)36047-36054
頁數8
期刊Journal of Biological Chemistry
284
發行號52
DOIs
出版狀態已發佈 - 十二月 25 2009

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