Suppression of proinflammatory cytokines in monocytes by a tetravalent guanylhydrazone
Article
Bianchi, M, Bloom, O, Raabe, T et al. (1996). Suppression of proinflammatory cytokines in monocytes by a tetravalent guanylhydrazone
. JOURNAL OF EXPERIMENTAL MEDICINE, 183(3), 927-936. 10.1084/jem.183.3.927
Bianchi, M, Bloom, O, Raabe, T et al. (1996). Suppression of proinflammatory cytokines in monocytes by a tetravalent guanylhydrazone
. JOURNAL OF EXPERIMENTAL MEDICINE, 183(3), 927-936. 10.1084/jem.183.3.927
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 extent to other LPS-induced responses. Here, we report that CNI-1493 suppressed the LPS-stimulated production of proinflammatory cytokines (tumor necrosis factor [TNF], interleukins 1β and 6, macrophage inflammatory proteins 1α and 1β) 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 β or the upregulation of major histocompatibility complex class II by interferon γ (IFN-γ). In contrast to the macrophage suppressive actions of dexamethasone, which are overridden in the presence of IFN-γ. CNI-1493 retained its suppressive effects even in the presence of IFN-γ. 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 previous 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.
