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-B-related "TF-B" promoter binding site. We find that TSA and four other HDACi (apicidin, MS-275, sodium butyrate, and valproic acid) all inhibit by ϳ90% TF activity and protein level induction in human umbilical vein endothelial cells stimulated by the physiologic

more »

... gonists tumor necrosis factor (TNF)-␣, interleukin-1␤, lipopolysaccharide, and HOSCN without affecting expression of the NF-B-regulated adhesion molecules ICAM-1 and E-selectin. TSA and butyrate also blunt TF induction ϳ50% in vitro in peripheral blood mononuclear cells and in vivo in thioglycolateelicited murine peritoneal macrophages. In human umbilical vein endothelial cells, TSA attenuates by ϳ70% TNF-␣ stimulation of TF mRNA transcription without affecting that of ICAM-1. By electrophoretic mobility shift assay analyses, TNF-␣ and lipopolysaccharide induce strong p65/p50 and p65/