Divergent effects of co-carcinogenic phorbol esters and a synthetic diacylglycerol on human neutrophil chemokinesis and granular enzyme secretion.
The effects of two co-carcinogenic phorbol esters (phorbol myristate acetate (PMA) and phorbol dibutyrate (PDBu] and a synthetic diacylglycerol (OAG, 1-oleoyl-2-acetyl-glycerol), which all stimulate protein kinase C, were compared with two inactive phorbol compounds (4 alpha-phorbol and 4 alpha-phorbol didecanoate (4 alpha-PDD)) on three functional properties of stimulated human polymorphonuclear leukocytes (PMNs): release of granular enzymes lysozyme and beta-glucuronidase, chemokinesis, and changes in cytoplasmic free calcium [Ca2+]i. PMA, PDBu and the diacylglycerol, OAG, all caused a dose-dependent and slow (max by 15 min) release of small amounts of lysozyme with much less beta-glucuronidase and no release of cytoplasmic lactate dehydrogenase. Release was unaffected by removal of extracellular Ca2+. PMA, PDBu and OAG inhibited random movement of the cells, did not cause chemokinesis and induced a slow reduction in the basal [Ca2+]i, as measured by the quin-2 method. PMA, PDBu and OAG increased the capacity of five independently-acting stimulants (N-formyl-Met-Leu-Phe, leukotriene B4, C5a des-Arg, platelet activating factor and A23187) to cause release of lysozyme and beta-glucuronidase but strongly inhibited PMN chemokinesis induced by the same five agents and reduced the stimulant-induced increases in [Ca2+]i. PMA was always more potent than PDBu and much more potent than OAG in eliciting these stimulatory or inhibitory effects on human PMNs. In all tests, 4 alpha-phorbol and 4 alpha-PDD were inactive. The results confirm that stimulation of the diacylglycerol/protein kinase C system in human PMN, either by active phorbol esters or the synthetic diacylglycerol, causes bidirectional effects on human PMN function. In particular, activation of the C-kinase causes inhibition of stimulated neutrophil motility, whereas the secretory functions of the cells are enhanced.
D002118:Calcium / Q000502:physiology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D003043:Cocarcinogenesis; D003594:Cytoplasmic Granules / Q000201:enzymology*; D004075:Diglycerides / Q000633:toxicity*; D005989:Glycerides / Q000633:toxicity*; D006801:Humans; D009113:Muramidase / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects* / Q000201:enzymology; D015240:Phorbol 12,13-Dibutyrate; D010703:Phorbol Esters / Q000633:toxicity*; D011493:Protein Kinase C / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity
D004075:Diglycerides; D005989:Glycerides; D010703:Phorbol Esters; D015240:Phorbol 12,13-Dibutyrate; C038237:1-oleoyl-2-acetylglycerol; D011493:Protein Kinase C; D009113:Muramidase; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium