Suppression of proinflammatory cytokines in monocytes by a tetravalent guanylhydrazone
Details
Serval ID
serval:BIB_290124E47DBC
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Suppression of proinflammatory cytokines in monocytes by a tetravalent guanylhydrazone
Journal
Journal of Experimental Medicine
ISSN
0022-1007 (Print)
Publication state
Published
Issued date
03/1996
Volume
183
Number
3
Pages
927-36
Notes
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S. --- Old month value: Mar 1
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S. --- Old month value: Mar 1
Abstract
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.
Keywords
Animals
Cell Line
Cytokines/antagonists & inhibitors/*biosynthesis
Dose-Response Relationship, Drug
Enzyme Induction
Humans
Hydrazones/*pharmacology
*Inflammation
Interferon Type II/biosynthesis
Interleukin-1/biosynthesis
Interleukin-6/biosynthesis
Kinetics
Lipopolysaccharides/antagonists & inhibitors/pharmacology
Macrophage Inflammatory Protein-1
Macrophages/drug effects/*immunology
Mice
Monocytes/drug effects/*immunology
Monokines/biosynthesis
Nitric Oxide/biosynthesis
Nitric Oxide Synthase/antagonists & inhibitors/*biosynthesis
Tumor Necrosis Factor-alpha/biosynthesis
Pubmed
Web of science
Open Access
Yes
Create date
25/01/2008 14:28
Last modification date
20/08/2019 14:08