Auranofin inhibits the activation pathways of polymorphonuclear leukocytes at multiple sites.
In order to characterize the mechanism by which the anti-rheumatic gold complex auranofin (AF) affects the functions of resting and activated polymorphonuclear leukocytes (PMN) the following studies were performed: (1) The effect of AF on the major processes involved in the respiratory burst of PMN: glucose transport and phosphorylation; hexose monophosphate (HMP) shunt activity in intact cells and in a cell-free system; superoxide production by particulate fractions and intact PMN measured as lucigenin-dependent chemiluminescence. (2) A comparison of the effects of AF added to the PMN before, at the time of, or subsequent to the stimulants [N-formyl-methionyl-leucyl phenylalanine (FMLP), concanavalin A (ConA), calcium ionophore (A23187) and phorbol myristate acetate (PMA)]. (3) The effect of AF on PMN activated by two stimulates (PMA, ConA) added sequentially. AF (0.1-10 microM) caused a dose-dependent inhibition of lucigenin-dependent chemiluminescence regardless of the activator (FMLP, ConA, A23187, PMA) when AF was added before the activator. In contrast, when AF was added to PMN after stimulation, it inhibited only the chemiluminescence of PMN stimulated by PMA. Furthermore, the chemiluminescence was largely unaffected by AF in sequentially activated PMN. The relative sensitivity to AF of the various processes studied indicates that blockade of the activation signal appears to be responsible for inhibition of the respiratory burst of PMN.
Rudkowski
R
R
Prince of Wales Children's Hospital, Randwick NSW, Australia.
Ziegler
J B
JB
Graham
G G
GG
Champion
G D
GD
D001310:Auranofin / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D003208:Concanavalin A / Q000494:pharmacology; D003847:Deoxyglucose / Q000378:metabolism; D006105:Granulomatous Disease, Chronic / Q000097:blood; D006801:Humans; D009247:NADH, NADPH Oxidoreductases / Q000097:blood; D019255:NADPH Oxidases; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D010427:Pentose Phosphate Pathway / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D013268:Stimulation, Chemical; D013481:Superoxides / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D003208:Concanavalin A; D013481:Superoxides; D001310:Auranofin; D003847:Deoxyglucose; D009247:NADH, NADPH Oxidoreductases; D019255:NADPH Oxidases; D013755:Tetradecanoylphorbol Acetate; D010100:Oxygen