ABSTRACT
1-O-Hexadecyl/octadecyl-2-acetyl-sn-glyceryl-3-phosphorylcholine (AGEPC), the acetylated alkyl phosphoglyceride known as platelet-activating factor, stimulated human neutrophil (PMN) exocytosis, migration, superoxide production and aggregation over a concentration range of 10(-10) to 10(-5) M. AGEPC-induced PMN exocytosis of azurophilic (myeloperoxidase and beta-glucuronidase) and specific (lactoferrin and lysozyme) lysosomal granules was rapid (T 1/2 = 20 sec), dependent on the presence of cytochalasin B, but was not associated with release of cytoplasmic LDH. As seen with the complement-derived peptide stimulus, C5a, AGEPC-initiated PMN enzyme release was dependent on temperature and cellular glycolysis but not on the presence of extracellular Ca++. When analyzed by gradient analysis, PMN migration caused by AGEPC was primarily chemotactic in nature. An unusual feature for both enzyme secretion and migration was a decrease in response between 10(-6) M and 10(-5) M AGEPC. This decreased responsiveness could be explained by rapid PMN desensitization occurring at high AGEPC concentrations, limiting the overall cellular response. Rapid desensitization for exocytosis was demonstrated in PMN stimulated with AGEPC in the absence of cytochalasin B. When cytochalasin B was added subsequently and PMN challenged with AGEPC or C5a, stimulus-specific desensitization to AGEPC but not C5a-induced lysosomal enzyme release occurred. PMN desensitized to C5a responded normally to a subsequent AGEPC challenge. Stimulation of all the PMN functions examined was markedly attenuated with removal of the 2-acetyl group from AGEPC (lyso GEPC). These results suggest that AGEPC stimulates a wide variety of human PMN responses by a receptor-like mechanism, dependent on the short chain fatty acid ester in the 2-position of the alkyl phosphoglyceride.
