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Pyrrolidine dithiocarbamate abrogates tissue factor (TF) expression by
endothelial cells: evidence implicating nuclear factor-kappa B in TF
induction by diverse agonists
CL Orthner, GM Rodgers and LA Fitzgerald
Plasma Derivatives Laboratory, American Red Cross Holland Laboratory,
Rockville, MD 20855, USA.
Tissue factor (TF), a 46-kD glycoprotein receptor for coagulation factors
VII and VIIa, is expressed on the surface of endothelial cells in response
to a variety of agonists and is thought to play an important role in
initiating the thrombosis associated with inflammation during infection,
sepsis, and organ transplant rejection. The induction of TF activity by
lipopolysaccharide (LPS) is regulated, at least partially, at a
transcriptional level and an LPS response element containing two activator
protein-1 sites and a nuclear factor- kappa B (NF kappa B)-like site has
been localized to the 5' flanking region of the TF gene by transfection
studies of TF promoter/reporter gene constructs. We have examined the
effect of pyrrolidine dithiocarbamate (PDTC), a specific inhibitor of the
NF kappa B pathway on the expression of the endogenous TF gene in human
umbilical vein endothelial cells (HUVEC). Preincubation of HUVEC for 60
minutes with PDTC inhibited LPS induction of TF activity on the cell
surface in a dose-dependent manner, with 50% inhibition occurring at 10
mumol/L PDTC and 100% inhibition at higher concentrations (> or = 100
mumol/L). Furthermore, PDTC inhibited TF expression in response to tumor
necrosis factor-alpha, interleukin-1 beta, and phorbol 12-myristate
13-acetate. The effect of PDTC was at the mRNA level, as seen by the
complete abrogation of the large increase in TF mRNA observed in
LPS-treated HUVEC. These results suggest that endothelial cell activation
by diverse agonists initiates intracellular signaling events that converge
upon a common pathway involving NF kappa B and, furthermore, that NF kappa
B activation is an obligatory step induction of TF.
Volume 86,
Issue 2,
pp. 436-443,
07/15/1995
Copyright © 1995 by The American Society of Hematology
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