Auranofin affects early events in human polymorphonuclear neutrophil activation by receptor-mediated stimuli.
Auranofin, a new oral antirheumatic gold compound, in concentrations achieved therapeutically, inhibits neutrophil phagocytosis, chemotaxis, chemiluminescence, reduction of cytochrome c, and release of lysosomal enzymes. To further characterize the mechanism by which auranofin affects neutrophils, we studied the effects of auranofin on unstimulated properties and functions of neutrophils as well as on rapidly stimulated functions. When examined by electron microscopy, 4 micrograms/ml of auranofin significantly decreased the number of visualized centriole-associated microtubules in resting cells. Furthermore, auranofin inhibited neutrophil spreading on glass and caused a decrease in negative surface charge (electrophoretic mobility). In addition, auranofin inhibited several fmet-leu-phe-stimulated responses such as shape change, increases in centriole-associated microtubules, decreases in surface charge, and elicited membrane potential changes (di-O-C5(3) dye response). Auranofin (1 micrograms/ml) inhibited fmet-leu-phe-stimulated superoxide and hydrogen peroxide production by 80% (p less than 0.05), and also increased the affinity of receptors for fmet-leu-phe (from Ka 0.035 to Ka 0.48, p less than 0.001). Auranofin also affected neutrophil responses to phorbol myristic acetate (PMA). The total amount of PMA-stimulated superoxide production was suppressed by as little as 0.4 micrograms/ml of auranofin, but the lag time for activation was shortened by low concentrations of auranofin (0.5 to 1 microgram/ml). Four micrograms per milliliter of auranofin suppressed the decrease in surface charge induced by PMA. However, auranofin did not influence superoxide production elicited by the ionophore A23187. The results indicate that auranofin affects the earliest detected responses in neutrophil activation by certain receptor-mediated stimuli.
D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001310:Auranofin; D006051:Aurothioglucose / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D006046:Gold; D017612:Gold Compounds / Q000378:metabolism; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D010101:Oxygen Consumption / Q000187:drug effects; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000502:physiology*; D044042:Receptors, Formyl Peptide
D000893:Anti-Inflammatory Agents; D017612:Gold Compounds; D011956:Receptors, Cell Surface; D044042:Receptors, Formyl Peptide; D006051:Aurothioglucose; D001310:Auranofin; D009240:N-Formylmethionine Leucyl-Phenylalanine; D006046:Gold