Synthesis of platelet-activating factor from human polymorphonuclear leukocytes: regulation and pharmacological approaches.
Human polymorphonuclears release a platelet-activating factor (PAF-acether) when challenged with various stimuli. PAF-acether is a mediator that is synthesized during cell activation in a process in which a phospholipase A2 and an acetyltransferase take part. These enzymes are finely regulated and accordingly PAF-acether release may be modulated. The authors have studied some of the transductory mechanisms which are triggered during cell stimulation and the effect of their pharmacological modulation on PAF-acether release. Theophylline, methylisobutylxanthine and dipyridamole, which block phosphodiesterase of cyclic nucleotides, induce a dose-dependent inhibition of PAF-acether release without affecting phagocytic uptake. Polyamines (dansylcadaverine, rimantadine and amantadine) reduced PAF-acether release and the phagocytic process in an order of potency similar to their ability to inhibit phospholipid methylation and the cholinephosphotransferase pathway. The calmodulin antagonist trifluoperazine induced a dose-dependent inhibition of PAF-acether release and acetyltransferase at concentrations from 10(-4) to 10(-5) M. Hence it appears that modulation of PAF-acether release can be obtained by different pharmacological blockades: phosphodiesterase of cyclic nucleotides, phospholipid metabolism and calcium-calmodulin.
D000123:Acetyltransferases / Q000378:metabolism; D002118:Calcium / Q000502:physiology; D000242:Cyclic AMP / Q000502:physiology; D006801:Humans; D008745:Methylation; D009504:Neutrophils / Q000378:metabolism*; D010713:Phosphatidylcholines / Q000096:biosynthesis; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010743:Phospholipids / Q000378:metabolism; D010972:Platelet Activating Factor / Q000096:biosynthesis*; D014268:Trifluoperazine / Q000494:pharmacology
D010713:Phosphatidylcholines; D010726:Phosphodiesterase Inhibitors; D010743:Phospholipids; D010972:Platelet Activating Factor; D014268:Trifluoperazine; D000242:Cyclic AMP; D000123:Acetyltransferases; D002118:Calcium