Histone deacetylase inhibitors decrease Toll-like receptor-mediated activation of proinflammatory gene expression by impairing transcription factor recruitment

Immunology. 2007 Dec;122(4):596-606. doi: 10.1111/j.1365-2567.2007.02678.x. Epub 2007 Jul 16.


Post-translational modifications of histone proteins are major mechanisms that modify chromatin structure and regulate gene expression in eukaryotes. Activation of histone acetyltransferases or inhibition of histone deacetylases (HDACs) is generally believed to allow chromatin to assume a more open state, permitting transcriptional activity. We report here the surprising observation that treatment of murine dendritic cells with the HDAC inhibitors trichostatin A (TSA) or suberoylanilide hydroxamic acid (SAHA) in non-apoptotic concentrations strongly inhibited induction of both interleukin-12 protein p40 (IL-12p40) mRNA and protein upon stimulation of Toll-like receptors (TLRs). Moreover, TLR-mediated up-regulation of costimulatory molecules was also inhibited. Up-regulation of tumour necrosis factor-alpha mRNA and protein in response to TLR agonists was only affected upon prolonged exposure to HDAC inhibitors and regulation of IL-1 beta was not affected. Similar effects were apparent in murine and human macrophages. Regarding the mode of action, HDAC inhibition increased the acetylation status at the IL-12p40 locus. Nevertheless, IL-12p40 chromatin remodelling, binding of Rel-A and IRF1 to the IL-12p40 promoter and transcriptional activation were abrogated. In contrast, HDAC inhibitors had no effects on upstream nuclear factor-kappaB and mitogen-activated protein kinase activation. Thus HDACs positively regulate the expression of a subset of cytokine genes by enabling transcription factor recruitment.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / drug effects
  • Cell Differentiation / immunology
  • Chromatin / metabolism
  • Cytokines / biosynthesis
  • Dendritic Cells / drug effects*
  • Dendritic Cells / immunology
  • Enzyme Inhibitors / pharmacology*
  • Gene Expression Regulation / drug effects*
  • Gene Expression Regulation / immunology
  • Histone Deacetylase Inhibitors*
  • Hydroxamic Acids / pharmacology
  • Inflammation Mediators / metabolism*
  • Interleukin-12 Subunit p40 / biosynthesis
  • Interleukin-12 Subunit p40 / genetics
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Reverse Transcriptase Polymerase Chain Reaction / methods
  • Toll-Like Receptors / immunology*
  • Transcription, Genetic / drug effects
  • Vorinostat


  • Chromatin
  • Cytokines
  • Enzyme Inhibitors
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Inflammation Mediators
  • Interleukin-12 Subunit p40
  • Toll-Like Receptors
  • trichostatin A
  • Vorinostat