Suppression of proinflammatory cytokines in monocytes by a tetravalent guanylhydrazone.

Détails

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Accès restreint UNIL
Etat: Public
Version: de l'auteur⸱e
Licence: Non spécifiée
ID Serval
serval:BIB_290124E47DBC
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Suppression of proinflammatory cytokines in monocytes by a tetravalent guanylhydrazone.
Périodique
The Journal of experimental medicine
Auteur⸱e⸱s
Bianchi M., Bloom O., Raabe T., Cohen P.S., Chesney J., Sherry B., Schmidtmayerova H., Calandra T., Zhang X., Bukrinsky M., Ulrich P., Cerami A., Tracey K.J.
ISSN
0022-1007 (Print)
ISSN-L
0022-1007
Statut éditorial
Publié
Date de publication
01/03/1996
Peer-reviewed
Oui
Volume
183
Numéro
3
Pages
927-936
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
Publication Status: ppublish
Résumé
An overproduction of proinflammatory cytokines by activated macrophages/monocytes mediates the injurious sequelae of inflammation, septic shock, tissue injury, and cachexia. We recently synthesized a tetravalent guanylhydrazone compound (CNI-1493) that inhibits cytokine-inducible arginine transport and nitric oxide (NO) production in macrophages, and protects mice against lethal endotoxemia and carrageenan-induced inflammation. During these investigations we noticed that CNI-1493 effectively prevented lipopolysaccharide (LPS)-induced NO production, even when added in concentrations 10-fold less than required to competitively inhibit L-arginine uptake, suggesting that the suppressive effects of this guanylhydrazone compound might extend to other LPS-induced responses. Here, we report that CNI-1493 suppressed the LPS-stimulated production of proinflammatory cytokines (tumor necrosis factor [TNF], interleukins 1beta and 6, macrophage inflammatory proteins 1alpha and 1beta) from human peripheral blood mononuclear cells. Cytokine suppression was specific, in that CNI-1493 did not inhibit either the constitutive synthesis of transforming growth factor beta or the upregulation of major histocompatibility complex class II by interferon gamma (IFN-gamma). In contrast to the macrophage suppressive actions of dexamethasone, which are overridden in the presence of IFN-gamma, CNI-1493 retained its suppressive effects even in the presence of IFN-gamma. The mechanism of cytokine-suppressive action by CNI-1493 was independent of extracellular L-arginine content and NO production and is not restricted to induction by LPS. As a selective inhibitor of macrophage activation that prevents TNF production, this tetravalent guanylhydrazone could be useful in the development of cytokine-suppressive agents for the treatment of diseases mediated by overproduction of cytokines.
Mots-clé
Animals, Cell Line, Chemokine CCL4, Cytokines/antagonists & inhibitors, Cytokines/biosynthesis, Dose-Response Relationship, Drug, Enzyme Induction, Humans, Hydrazones/pharmacology, Inflammation, Interferon-gamma/biosynthesis, Interleukin-1/biosynthesis, Interleukin-6/biosynthesis, Kinetics, Lipopolysaccharides/antagonists & inhibitors, Lipopolysaccharides/pharmacology, Macrophage Inflammatory Proteins, Macrophages/drug effects, Macrophages/immunology, Mice, Monocytes/drug effects, Monocytes/immunology, Monokines/biosynthesis, Nitric Oxide/biosynthesis, Nitric Oxide Synthase/antagonists & inhibitors, Nitric Oxide Synthase/biosynthesis, Tumor Necrosis Factor-alpha/biosynthesis
Pubmed
Web of science
Open Access
Oui
Création de la notice
25/01/2008 14:28
Dernière modification de la notice
09/08/2024 14:01
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