Phorbol esters inhibit the fMet-Leu-Phe- and leukotriene B4-stimulated calcium mobilization and enzyme secretion in rabbit neutrophils

Abstract

The tumor co-promoter phorbol 12, myristate 13, acetate (PMA) has previously been shown to stimulate several of the characteristic functions (aggregation, degranulation, and the oxidative burst) of polymorphonuclear leukocytes (neutrophils). We describe here a novel feature of the action of PMA on neutrophils, namely its ability to inhibit the chemotactic factor-induced increased in the enzyme secretion and in the intracellular concentration of free calcium. The inhibition is maximal within 3 min of the addition of PMA and is concentration-dependent (IC50 = 8.5 ng/ml). The site of action of PMA is distal to the binding of the chemotactic factors. PMA inhibits both the release of intracellular calcium and the permeability changes to calcium induced by chemotactic factors, but does not affect the stimulation of the rate of influx of sodium produced by the same agents. The PMA analog 4 alpha-phorbol 12, 13-didecanoate, which lack tumorigenicity and the ability to activate the calcium- and phospholipid-dependent protein kinase (protein kinase C), does not inhibit any of the above fMet-Leu-Phe-stimulated neutrophil functions. The present results thus demonstrate that phorbol esters, either directly or indirectly, possibly through the activation of protein kinase C, inhibit the signal(s) responsible for the stimulated mobilization of calcium in rabbit neutrophils.