Nonsteroidal antiinflammatory drugs exert differential effects on neutrophil function and plasma membrane viscosity. Studies in human neutrophils and liposomes.
Nonsteroidal antiinflammatory drugs (NSAIDs) inhibit neutrophil functions via mechanisms separate from their capacity to inhibit prostaglandin synthesis. We have studied discrete events in the process of signal transduction: NSAIDs but not a related analgesic drug (acetaminophen), inhibited aggregation in response to the chemoattractants f-Met-Leu-Phe (FMLP), leukotriene B4, and C5a. NSAIDs, but not acetaminophen, inhibited binding of radiolabeled FMLP to purified neutrophil membranes. Gpp(NH)p, a GTPase insensitive analog of GTP, also inhibited the binding of FMLP but, paradoxically, enhanced superoxide anion generation and lysozyme release. The inhibition of ligand binding by NSAIDs did not correlate with their capacity to inhibit FMLP-induced increments in diacylglycerol (DG): piroxicam, but not salicylate effectively inhibited appearance of label ([3H]arachidonate, [14C]glycerol) in DG. Finally, NSAIDs exerted differential effects on the viscosity of neutrophil plasma membranes and multilamellar vesicles (liposomes): membrane viscosity was increased by piroxicam and indomethacin, decreased by salicylate, and unaffected by acetaminophen. Thus, the different effects of NSAIDs on discrete pathways are not due to their shared capacity to reduce ligand binding but rather to a capacity to uncouple postreceptor signaling events that depend upon the state of membrane fluidity.
Abramson
S B
SB
Division of Rheumatology, NYU Medical Center, New York 10016.
Cherksey
B
B
Gude
D
D
Leszczynska-Piziak
J
J
Philips
M R
MR
Blau
L
L
Weissmann
G
G
D000082:Acetaminophen / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D015703:Antigens, CD / Q000032:analysis; D002449:Cell Aggregation / Q000187:drug effects; D004075:Diglycerides / Q000096:biosynthesis; D006150:Guanine Nucleotides / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008081:Liposomes; D008560:Membrane Fluidity / Q000187:drug effects*; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000378:metabolism / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects*; D011869:Radioligand Assay; D011951:Receptors, Complement / Q000096:biosynthesis / Q000378:metabolism; D017463:Receptors, Complement 3b; D012969:Sodium Fluoride / Q000494:pharmacology; D014783:Viscosity
D000894:Anti-Inflammatory Agents, Non-Steroidal; D015703:Antigens, CD; D004075:Diglycerides; D006150:Guanine Nucleotides; D008081:Liposomes; D011951:Receptors, Complement; D017463:Receptors, Complement 3b; D000082:Acetaminophen; D009240:N-Formylmethionine Leucyl-Phenylalanine; D012969:Sodium Fluoride