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Pyrrolidine dithiocarbamate inhibits the production of interleukin-6,
interleukin-8, and granulocyte-macrophage colony-stimulating factor by
human endothelial cells in response to inflammatory mediators: modulation
of NF-kappa B and AP-1 transcription factors activity
C Munoz, D Pascual-Salcedo, MC Castellanos, A Alfranca, J Aragones, A Vara, MJ Redondo and MO de Landazuri
Servicio de Inmunologia, Hospital de la Princesa, Universidad Autonoma de
Madrid, Spain.
Endothelial cells (EC) play a key role in the inflammatory response, both
by the production of proinflammatory cytokines and by their interaction
with leukocytes. Molecular genetic analysis has demonstrated that
functional NF-kappa B sites are involved in the transcription of
interleukin-6 (IL-6), IL-8, and granulocyte-macrophage colony-stimulating
factor (GM-CSF) genes in response to inflammatory mediators. Thus, we have
explored the effect of two inhibitors of the NF-kappa B activation,
pyrrolidine dithiocarbamate (PDTC) and N- acetylcysteine (NAC), on the
production of these cytokines by EC. Both PDTC and NAC inhibited, in a
dose-dependent manner, the synthesis of IL- 6, IL-8, and GM-CSF induced by
tumor necrosis factor (TNF)-alpha or bacterial lipopolysaccharides (LPS) in
human umbilical vein endothelial cells (HUVEC). PDTC appeared to prevent
IL-6, IL-8, and GM-CSF gene transcription, as it blocked the induction of
specific mRNA by TNF- alpha or LPS. The TNF-alpha mediated transcriptional
activation of a chloramphenicol acetyltransferase (CAT) plasmid containing
three copies of the -72 kappa B binding site from the IL-6 promoter was
abrogated by PDTC. According to transfection experiments, electrophoretic
mobility shift assays (EMSA) demonstrated that the antioxidant prevented
the induction of NF-kappa B DNA-binding activity by TNF-alpha. Under the
same conditions, PDTC by itself or in combination with TNF-alpha, enhanced
the DNA-binding activity of AP-1, as well as c-fos and c-jun mRNA levels.
Altogether, these results indicate that the antioxidant PDTC specifically
inhibits the transcription of IL-6, IL-8, and GM-CSF genes through the
inhibition of the NF-kappa B activation, while increasing the expression of
AP-1. Our data make evident the antiinflammatory and immunoregulatory
potential of the pharmacological inhibition of the NF-kappa B activation.
In addition, PDTC and related molecules may be a useful tool to explore the
expression of genes involved in the inflammatory response.
Volume 88,
Issue 9,
pp. 3482-3490,
11/01/1996
Copyright © 1996 by The American Society of Hematology
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