Pharmacologic modulation of TNF production by endotoxin stimulated macrophages: in vitro and in vivo effects of auranofin and other chrysotherapeutic compounds.
The gold compounds, auranofin, sodium aurothiomalate, and triethyl gold phosphine have been demonstrated to inhibit various effector functions associated with monocyte-macrophage populations. Incubation of human peripheral blood monocytes and murine peritoneal macrophages with auranofin or triethyl gold phosphine inhibited TNF production in lipopolysaccharide [LPS] stimulated murine peritoneal macrophages. The inhibitory effect of auranofin and triethyl gold phosphine on LPS stimulated monokine production was reversible when these compounds were incubated with macrophage cultures at concentrations between 0.1-0.5 micrograms/ml. These compounds also inhibited both TNF and IL-1 production by human peripheral blood monocytes. Sodium aurothiomalate at these concentrations had no inhibitory effect on TNF or IL-1 production. Auranofin and triethyl gold phosphine also inhibited TNF production in vivo when compounds were administered orally or intraperitoneally 2 hours prior to a lethal dose of endotoxin. Serum TNF levels from Balb/c mice were significantly reduced when animals were predosed with 1-25 mg/kg of auranofin. The data suggest that the inhibition of TNF production by activated macrophages may contribute to the therapeutic role of gold compounds in the management of chronic inflammatory disease.
Evans
G F
GF
Department of Immunology, Eli Lilly and Company, Indianapolis, IN 46285.
Zuckerman
S H
SH
D000818:Animals; D001310:Auranofin / Q000494:pharmacology*; D003907:Dexamethasone / Q000494:pharmacology*; D005260:Female; D006052:Gold Sodium Thiomalate / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000096:biosynthesis / Q000097:blood; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis*
D007375:Interleukin-1; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D006052:Gold Sodium Thiomalate; D001310:Auranofin; D003907:Dexamethasone