Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 284, Issue 52, Pages 36047-36054Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M109.025387
Keywords
-
Categories
Funding
- Wellcome Trust [076472/Z/05/Z]
- Medical Research Council [G0401662]
- Medical Research Council [G0401662] Funding Source: researchfish
- MRC [G0401662] Funding Source: UKRI
Ask authors/readers for more resources
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-1 beta-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) 1 alpha to a HIF response element at position -320, but not HIF-1 beta or HIF-2 alpha, results in reduced polymerase II binding at the site, leading to reduced promoter activity of HDAC2. Our results suggest that activation of HIF-1 alpha by hypoxia decreases HDAC2 levels, resulting in amplified inflammation and corticosteroid resistance.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available