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Platelet-activating factor synthesis and phospholipid remodelling in human neutrophils.
Human neutrophils synthesize platelet-activating factor and leukotriene B4 when exposed to calcium ionophore A23187. The role of protein kinase C in the synthesis of these autacoids was examined. Phorbol 12-myristare-13-acetate (PMA), a direct activator of protein kinase C, did not directly stimulate autacoid synthesis, but enhanced the synthesis of these autacoids in cells stimulated with calcium ionophore A23187. The protein kinase C inhibitors stearoylamine, palmitoylcarnitine, and springosine, prevented A23187-induced PAF and LTB4 synthesis. This inhibition took place at the common step in PAF and LTB4 synthesis: release of their precursors from phospholipid stores via a phospholipase A2-like activity; protein kinase C activity was not required for subsequent metabolism of free arachidonate. A23187 also stimulated incorporation of noneicosanoid-precursor fatty acids into phosphatidylcholine in parallel to its stimulation of PAF synthesis. This was due to the activation of Lands deacylation/reacylation cycle. Deacylation was accomplished by a phospholipase A2 activity that appeared to utilize both diacyl and alkylacyl phosphatidylcholine. The 1-O-alkylglycerophosphocholine (GPC) thus generated was rapidly acetylated by stimulated acyltransferase activity to form PAF. Reacylation of 1-acylGPC, as well as the remaining 1-O-alkylGPC, was accomplished by a stimulated acyltransferase activity that did not employ arachidonylCoA as a substrate. Finally, the regulation of a stimulatable phospholipase D was examined in neutrophils. Protein kinase C activators may activate this enzyme, resulting in the potential generation of second messengers, such as phosphatidic acid, but protein kinase C activation is not required for phospholipase D activity. The fungal metabolite, wortmannin, inhibited receptor-mediated activation of phospholipase D. A model of phospholipase D activation is presented.
University of Utah;
Protein Kinase C; Signal Transduction; Immunology;
Digital reproduction of “Platelet-activating factor synthesis and phospholipid remodelling in human neutrophils.” Spencer S. Eccles Health Sciences Library. Print version of “Platelet-activating factor synthesis and phospholipid remodelling in human neutrophils.” available at J. Willard Marriott Library Special Collection. QP6.5 1989 .R44