Histone deacetylase 3, a class I histone deacetylase, suppresses MAPK11-mediated activating transcription factor-2 activation and represses TNF gene expression

J Immunol. 2004 Sep 15;173(6):3979-90. doi: 10.4049/jimmunol.173.6.3979.

Abstract

During inflammatory events, the induction of immediate-early genes, such as TNF-alpha, is regulated by signaling cascades including the JAK/STAT, NF-kappaB, and the p38 MAPK pathways, which result in phosphorylation-dependent activation of transcription factors. We observed the direct interaction of histone deacetylase (HDAC) 3, a class I histone deacetylase, with MAPK11 (p38 beta isoform) by West-Western-based screening analysis, pull-down assay, and two-hybrid system analysis. Results further indicated that HDAC3 decreases the MAPK11 phosphorylation state and inhibits the activity of the MAPK11-dependent transcription factor, activating transcription factor-2 (ATF-2). LPS-mediated activation of ATF-2 was inhibited by HDAC3 in a time- and dose-dependent manner. Inhibition of HDAC3 expression by RNA interference resulted in increased ATF-2 activation in response to LPS stimulation. In agreement with decreased ATF-2 transcriptional activity by HDAC3, HDAC3-repressed TNF gene expression, and TNF protein production observed in response to LPS stimulation. Therefore, our results indicate that HDAC3 interacts directly and selectively with MAPK11, represses ATF-2 transcriptional activity, and acts as a regulator of TNF gene expression in LPS-stimulated cells, especially in mononuclear phagocytes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 2
  • Animals
  • COS Cells
  • Cell Line, Tumor
  • Cyclic AMP Response Element-Binding Protein / antagonists & inhibitors*
  • Cyclic AMP Response Element-Binding Protein / genetics
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • Down-Regulation / genetics
  • Down-Regulation / immunology*
  • Gene Silencing / immunology*
  • Histone Deacetylases / classification
  • Histone Deacetylases / genetics
  • Histone Deacetylases / physiology*
  • Humans
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / physiology
  • Lipopolysaccharides / antagonists & inhibitors
  • Lipopolysaccharides / pharmacology
  • Mitogen-Activated Protein Kinase 11
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / physiology*
  • Monocytes / enzymology
  • Monocytes / immunology
  • Monocytes / metabolism
  • Peptide Fragments / genetics
  • Peptide Fragments / physiology
  • Repressor Proteins / classification
  • Repressor Proteins / genetics
  • Repressor Proteins / physiology
  • Transcription Factors / antagonists & inhibitors*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transfection
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors*
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Tumor Necrosis Factor-alpha / genetics*
  • U937 Cells

Substances

  • ATF2 protein, human
  • Activating Transcription Factor 2
  • Cyclic AMP Response Element-Binding Protein
  • Isoenzymes
  • Lipopolysaccharides
  • Peptide Fragments
  • Repressor Proteins
  • Transcription Factors
  • Tumor Necrosis Factor-alpha
  • Mitogen-Activated Protein Kinase 11
  • Mitogen-Activated Protein Kinases
  • Histone Deacetylases
  • histone deacetylase 3