Pharmacologic modulation of TNF production by endotoxin stimulated macrophages:In vitro andin vivo effects of auranofin and other chrysotherapeutic compounds

Abstract

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.

Intramuscular gold decreases cytokine expression and macrophage numbers in the rheumatoid synovial membrane.

“…Recently, it has been shown that SAT will accelerate the in vitro maturation of MONO to MAC with a concomitant decrease in IL-1 production. '2 13 Thus there is now the possibility to relate the therapeutic benefit with changes in expression of cytokines and the relative contribution of inflammatory MONO and downregulatory MAC within the synovial cell populations.…”

Endotoxin tolerance: independent regulation of interleukin-1 and tumor necrosis factor expression

“…Elevations in serum TNF or IL-1 or both have been demonstrated in patients with septic shock, lupus, rheumatoid arthritis, parasitic infections, and cancer and in burn models (1, 7, 13, 17, 22-24, 32, 36, 40) and in animal models of endotoxinor bacterium-induced shock (6,9,11,16,25,37,39,43,46). While regulation of TNF and IL-1 by exogenous glucocorticoids (5,9,39,43,46), prostaglandin E2 (19,31), protein kinase C antagonists (18), and gold salts (10) has been reported, the role of endogenous mediators in regulating IL-1 and TNF synthesis is less clear. The ability of IL-1 and TNF to stimulate pituitary adrenocorticotropin secretion and the resulting release of corticosterone by the adrenals have suggested a role for the neuroendocrine axis in modulating cytokine production (2-4, 30,33,38,46).…”

Effects of Gold Nanoparticles and Gold Anti-Arthritic Compounds on Inflammation Marker Expression in Macrophages

“…The above results contradict some reports in the literature that showed aurothiomalate has a small inhibitory effect on LPS-induced TNF production in human PBMCs. [71][72][73] A possible explanation for this difference could be that the experiments described here were performed using a murine macrophage cell line, as opposed to PBMCs isolated directly from humans [72,73] or mice. [71] It could also arise from differences in methodology, such as differences in the length of the pre-incubation period, and use of different LPS concentrations.…”

“…[71][72][73] A possible explanation for this difference could be that the experiments described here were performed using a murine macrophage cell line, as opposed to PBMCs isolated directly from humans [72,73] or mice. [71] It could also arise from differences in methodology, such as differences in the length of the pre-incubation period, and use of different LPS concentrations. [71][72][73] It should also be noted, however, that within the literature there are reports that suggest that aurothiomalate has no effect on production of TNF.…”

“…[71] It could also arise from differences in methodology, such as differences in the length of the pre-incubation period, and use of different LPS concentrations. [71][72][73] It should also be noted, however, that within the literature there are reports that suggest that aurothiomalate has no effect on production of TNF. For example, one study that also investigated human PBMCs (from RA patients) showed that aurothiomalate does not alter LPS-stimulated TNF production, [74] whilst another reported that the compound does not affect TNF mRNA levels in LPS-stimulated murine macrophages.…”