Histone deacetylase 7 promotes Toll-like receptor 4-dependent proinflammatory gene expression in macrophages

J Biol Chem. 2013 Aug 30;288(35):25362-25374. doi: 10.1074/jbc.M113.496281. Epub 2013 Jul 12.


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.

Keywords: Histone Deacetylase; Hypoxia-inducible Factor (HIF); Inflammation; Macrophages; Toll-like Receptor (TLR).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alcohol Oxidoreductases / genetics
  • Alcohol Oxidoreductases / metabolism
  • Animals
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Gene Expression Regulation*
  • HEK293 Cells
  • Histone Deacetylases / genetics
  • Histone Deacetylases / metabolism*
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Inflammation / genetics
  • Inflammation / metabolism
  • Inflammation / pathology
  • Lipopolysaccharides / pharmacology
  • Macrophages / metabolism*
  • Macrophages / pathology
  • Mice
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Toll-Like Receptor 4 / agonists
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / metabolism*


  • DNA-Binding Proteins
  • HIF1A protein, human
  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Lipopolysaccharides
  • TLR4 protein, human
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • Alcohol Oxidoreductases
  • C-terminal binding protein
  • HDAC7 protein, human
  • Hdac7 protein, mouse
  • Histone Deacetylases