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Histone deacetylase 7 promotes Toll-like receptor 4-dependent proinflammatory gene expression in macrophages.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2013 Aug 30; Vol. 288 (35), pp. 25362-25374. Date of Electronic Publication: 2013 Jul 12. - Publication Year :
- 2013
-
Abstract
- Broad-spectrum inhibitors of histone deacetylases (HDACs) constrain Toll-like receptor (TLR)-inducible production of key proinflammatory mediators. Here we investigated HDAC-dependent inflammatory responses in mouse macrophages. Of the classical Hdacs, Hdac7 was expressed at elevated levels in inflammatory macrophages (thioglycollate-elicited peritoneal macrophages) as compared with bone marrow-derived macrophages and the RAW264 cell line. Overexpression of a specific, alternatively spliced isoform of Hdac7 lacking the N-terminal 22 amino acids (Hdac7-u), but not the Refseq Hdac7 (Hdac7-s), promoted LPS-inducible expression of Hdac-dependent genes (Edn1, Il-12p40, and Il-6) in RAW264 cells. A novel class IIa-selective HDAC inhibitor reduced recombinant human HDAC7 enzyme activity as well as TLR-induced production of inflammatory mediators in thioglycollate-elicited peritoneal macrophages. Both LPS and Hdac7-u up-regulated the activity of the Edn1 promoter in an HDAC-dependent fashion in RAW264 cells. A hypoxia-inducible factor (HIF) 1 binding site in this promoter was required for HDAC-dependent TLR-inducible promoter activity and for Hdac7- and HIF-1α-mediated trans-activation. Coimmunoprecipitation assays showed that both Hdac7-u and Hdac7-s interacted with HIF-1α, whereas only Hdac7-s interacted with the transcriptional repressor CtBP1. Thus, Hdac7-u positively regulates HIF-1α-dependent TLR signaling in macrophages, whereas an interaction with CtBP1 likely prevents Hdac7-s from exerting this effect. Hdac7 may represent a potential inflammatory disease target.
- Subjects :
- Alcohol Oxidoreductases genetics
Alcohol Oxidoreductases metabolism
Animals
DNA-Binding Proteins genetics
DNA-Binding Proteins metabolism
HEK293 Cells
Histone Deacetylases genetics
Humans
Hypoxia-Inducible Factor 1, alpha Subunit genetics
Hypoxia-Inducible Factor 1, alpha Subunit metabolism
Inflammation genetics
Inflammation metabolism
Inflammation pathology
Lipopolysaccharides pharmacology
Macrophages pathology
Mice
Signal Transduction drug effects
Signal Transduction genetics
Toll-Like Receptor 4 agonists
Toll-Like Receptor 4 genetics
Gene Expression Regulation
Histone Deacetylases metabolism
Macrophages metabolism
Toll-Like Receptor 4 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 288
- Issue :
- 35
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 23853092
- Full Text :
- https://doi.org/10.1074/jbc.M113.496281