Evidence for mediation of acetyl glyceryl ether phosphorylcholine stimulation of adenosine 3',5'-(cyclic)monophosphate levels in human polymorphonuclear leukocytes by leukotriene B4.
Acetyl glyceryl ether phosphorylcholine induces human neutrophil aggregation. Incubation of neutrophils with either prostaglandin I2, or the cyclic AMP-dependent phosphodiesterase inhibitor, RO 20-1724 before the addition of PAF-acether attenuates subsequent aggregation. Paradoxically, a small elevation in cyclic AMP is observed coincident with the initiation of PAF-acether-stimulated aggregation. The elevation in cyclic AMP in response to PAF-acether is amplified by RO 20-1724, and the magnitude of the response is dependent upon the concentration of PAF-acether. The elevation in cyclic AMP is not due to prostaglandins, because indomethacin actually enhances the elevation in cyclic AMP induced by PAF-acether. The involvement of the neutrophil 5-lipoxygenase, and subsequent leukotriene B4 synthesis, is suggested by the observation that 5-lipoxygenase inhibitors limit both the elevation in cyclic AMP induced by PAF-acether, and the indomethacin enhancement. This indirect evidence is supported by the fact that leukotriene B4 itself elevates neutrophil cyclic AMP levels in intact cells, and stimulates the adenylate cyclase in broken cell preparations. Although the elevation in cyclic AMP induced by either PAF-acether or leukotriene B4 is coincident with the onset of neutrophil aggregation, it is not obligatory for aggregation. The adenylate cyclase inhibitor 2',5'-dideoxyadenosine blocks the PAF-acether-stimulated increase in cyclic AMP, and actually enhances aggregation. It is suggested that the increase in cyclic AMP observed after the addition of PAF-acether is due to concomitant leukotriene B4 synthesis, and is not obligatory for neutrophil aggregation, but is actually part of a feed-back regulatory system through which PAF-acether and leukotriene B4 can limit their own activity in neutrophils.
D000262:Adenylyl Cyclases / Q000097:blood; D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000097:blood; D000242:Cyclic AMP / Q000097:blood*; D004789:Enzyme Activation; D004837:Epinephrine / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D007975:Leukotriene B4 / Q000096:biosynthesis / Q000494:pharmacology*; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D010972:Platelet Activating Factor / Q000031:analogs & derivatives* / Q000494:pharmacology; D012969:Sodium Fluoride / Q000494:pharmacology; D013552:Swine
D001095:Arachidonic Acids; D010972:Platelet Activating Factor; D007975:Leukotriene B4; D016718:Arachidonic Acid; C026613:1-0-octadecyl 2-0-acetyl sn-glycero-3-phosphorylcholine; D012969:Sodium Fluoride; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D004837:Epinephrine