Histone deacetylase inhibitors suppress TF-κB-dependent agonist-driven tissue factor expression in endothelial cells and monocytes

Jianguo Wang, Shawn A. Mahmud, Peter B. Bitterman, Yuqing Huo, Arne Slungaard

Research output: Contribution to journalArticle

51 Scopus citations

Abstract

Histone deacetylase inhibitors (HDACi), such as trichostatin A (TSA), can regulate gene expression by promoting acetylation of histones and transcription factors. Human tissue factor (TF) expression is partly governed by a unique, NF-κB-related "TF-κB" promoter binding site. We find that TSA and four other HDACi (apicidin, MS-275, sodium butyrate, and valproic acid) all inhibit by ∼90% TF activity and protein level induction in human umbilical vein endothelial cells stimulated by the physiologic agonists tumor necrosis factor (TNF)-α, interleukin-1β, lipopolysaccharide, and HOSCN without affecting expression of the NF-κB-regulated adhesion molecules ICAM-1 and E-selectin. TSA and butyrate also blunt TF induction ∼50% in vitro in peripheral blood mononuclear cells and in vivo in thioglycolate-elicited murine peritoneal macrophages. In human umbilical vein endothelial cells, TSA attenuates by ∼70% TNF-α stimulation of TF mRNA transcription without affecting that of ICAM-1. By electrophoretic mobility shift assay analyses, TNF-α and lipopolysaccharide induce strong p65/p50 and p65/ c-Rel heterodimer binding to both NF-κB and TF-κB probes. TSA nearly abolishes TF-κB binding without affecting NF-κB binding. A chromatin immunoprecipitation assay and a promoter-luciferase reporter system confirm that TSA inhibits TF-κB but not NF-κB activation. Chromatin immunoprecipitation and small interfering RNA inhibitor studies demonstrate that HDAC3 plays a significant role in TNF-α-mediated TF induction. Thus, HDACi transcriptionally inhibit agonist-induced TF expression in endothelial cells and monocytes by a TF-αB- and HDAC3-dependent mechanism. We conclude that histone deacetylases, particularly HDAC3, play a hitherto unsuspected role in regulating TF expression and raise the possibility that HDACi might be a novel therapy for thrombotic disorders.

Original languageEnglish (US)
Pages (from-to)28408-28418
Number of pages11
JournalJournal of Biological Chemistry
Volume282
Issue number39
DOIs
StatePublished - Sep 28 2007

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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