Acetylglycerylether phosphorylcholine-(AGEPC) and leukotriene B4-stimulated cyclic AMP levels in human polymorphonuclear leukocytes.
It seems paradoxical that AGEPC induces a transient rise in cyclic AMP, yet the preincubation of neutrophils with agents that elevate cyclic AMP actually inhibits AGEPC-induced aggregation. However, similar transient elevations in cyclic AMP are observed using other stimulators of PMN function such as fmet-leu-phe, C5a (22), immune complexes (24), and phagocytosable particles (11). Elevations in cyclic AMP by PGE1, PGI2, dibutyryl cyclic AMP, and phosphodiesterase inhibitors, before the addition of an agonist, also blocked subsequent neutrophil activation in the above studies. Thus, these observations are not unique to AGEPC. However, the finding that the cyclooxygenase inhibitor indomethacin enhanced AGEPC-stimulated cyclic AMP accumulation is a novel observation and suggests that some oxygenated derivative of the 5-lipoxygenase pathway is responsible for the increase in cyclic AMP. The evidence for the association of the spike in cyclic AMP and the 5-lipoxygenase is strengthened by the observation that the 5-lipoxygenase inhibitor U-60257 attenuates the AGEPC-induced spike in cyclic AMP. It should be noted that U-60257 does not antagonize LTB4-stimulated cyclic AMP accumulation and has no direct influence on the neutrophil adenylate cyclase. The final correlation of the spike in cyclic AMP and the 5-lipoxygenase is made by the fact that LTB4 itself stimulates cyclic AMP levels in intact neutrophils as well as the adenylate cyclase in cell homogenates. As is the case with AGEPC, the transient spike in cyclic AMP induced by LTB4 is coincident with the onset of neutrophil aggregation. However, it is clear that the spike in neutrophil cyclic AMP induced by AGEPC can be dissociated from neutrophil aggregation.(ABSTRACT TRUNCATED AT 250 WORDS)
D000262:Adenylyl Cyclases / Q000378:metabolism; D001091:Arachidonate Lipoxygenases; D002449:Cell Aggregation / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors; D011464:Epoprostenol / Q000494:pharmacology / Q000031:analogs & derivatives; D005246:Feedback; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D007975:Leukotriene B4 / Q000494:pharmacology*; D016859:Lipoxygenase Inhibitors; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D010972:Platelet Activating Factor / Q000494:pharmacology*
D016861:Cyclooxygenase Inhibitors; D016859:Lipoxygenase Inhibitors; D010972:Platelet Activating Factor; D007975:Leukotriene B4; D011464:Epoprostenol; D000242:Cyclic AMP; D001091:Arachidonate Lipoxygenases; D000262:Adenylyl Cyclases; C035296:piriprost; D007213:Indomethacin