Non-steroidal anti-inflammatory drugs: effects on a GTP binding protein within the neutrophil plasma membrane

Sodium salicylate and other non-steroidal anti-inflammatory drugs (NSAIDs) inhibit neutrophil functions via unknown mechanisms. To examine their site of action in the neutrophil we have studied discrete events within the plasma membrane which depend upon the normal function of a GTP binding protein (G protein). We demonstrated that sodium salicylate and piroxicam inhibit neutrophil activation in response to stimuli which require signal transduction via a G protein (e.g. formyl-methionine-leucine-phenylalanine) but have no effect on stimuli which do not (e.g. phorbol myristate acetate, ionomycin). NSAIDs blocked the ADP-ribosylation of the pertussis toxin substrate in human neutrophils. This effect was associated with the capacity of NSAIDs to block pertussis toxin-dependent inhibition of neutrophil functions. Finally, NSAIDs inhibited the binding of GTP gamma S, a stable analog of GTP, to purified neutrophil membrane preparations. The data indicate that salicylate and other NSAIDs interact with a G protein in the neutrophil plasmalemma and thereby uncouple post-receptor signaling events.