Suppression of proinflammatory cytokines in monocytes by a tetravalent guanylhydrazone.
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.
Bianchi
M
M
Department of Surgery, North Shore University Hospital, Manhasset, New York 11030, USA.
Bloom
O
O
Raabe
T
T
Cohen
P S
PS
Chesney
J
J
Sherry
B
B
Schmidtmayerova
H
H
Calandra
T
T
Zhang
X
X
Bukrinsky
M
M
Ulrich
P
P
Cerami
A
A
Tracey
K J
KJ
D000818:Animals; D002460:Cell Line; D054407:Chemokine CCL4; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology*; D007249:Inflammation; D007371:Interferon-gamma / Q000096:biosynthesis; D007375:Interleukin-1 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D007700:Kinetics; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D019402:Macrophage Inflammatory Proteins; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D009000:Monocytes / Q000187:drug effects / Q000276:immunology*; D015846:Monokines / Q000096:biosynthesis; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D000813:Anilides; D006146:Guanidines
D054407:Chemokine CCL4; D016207:Cytokines; D006835:Hydrazones; D007371:Interferon-gamma; D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D019402:Macrophage Inflammatory Proteins; D015846:Monokines; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D014409:Tumor Necrosis Factor-alpha; C097256:semapimod; D000813:Anilides; D006146:Guanidines