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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.
Blood. 1996 Nov 01; 88(9):3482-90.Blood

Abstract

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.

Authors+Show Affiliations

Servicio de Inmunología, Hospital de la Princesa, Universidad Autónoma de Madrid, Spain.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

8896414

Citation

Muñoz, C, et al. "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." Blood, vol. 88, no. 9, 1996, pp. 3482-90.
Muñoz C, Pascual-Salcedo D, Castellanos MC, et al. 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. Blood. 1996;88(9):3482-90.
Muñoz, C., Pascual-Salcedo, D., Castellanos, M. C., Alfranca, A., Aragonés, J., Vara, A., Redondo, J. M., & de Landázuri, M. O. (1996). 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. Blood, 88(9), 3482-90.
Muñoz C, et al. 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. Blood. 1996 Nov 1;88(9):3482-90. PubMed PMID: 8896414.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Muñoz,C, AU - Pascual-Salcedo,D, AU - Castellanos,M C, AU - Alfranca,A, AU - Aragonés,J, AU - Vara,A, AU - Redondo,J M, AU - de Landázuri,M O, PY - 1996/11/1/pubmed PY - 1996/11/1/medline PY - 1996/11/1/entrez SP - 3482 EP - 90 JF - Blood JO - Blood VL - 88 IS - 9 N2 - 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. SN - 0006-4971 UR - https://www.unboundmedicine.com/medline/citation/8896414/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_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-4971(20)61362-3 DB - PRIME DP - Unbound Medicine ER -