PHORBOL ESTERS INHIBIT THE FMET-LEU-PHE-KOTRIENE AND LEUKOTRIENE B4-STIMULATED CALCIUM MOBILIZATION AND ENZYME-SECRETION IN RABBIT NEUTROPHILS

  • 1 January 1985
    • journal article
    • research article
    • Vol. 260  (4) , 2125-2131
Abstract
The tumor co-promoter phorbol 12, myristate 13, acetate (PMA) was previously shown to stimulate several of the characteristic functions (aggregation, degranulation and the oxidative burst) of polymorphonuclear leukocytes (neutrophils). A novel feature of the action of PMA on neutrophils, i.e., its ability to inhibit the chemotactic factor-induced increases in the enzyme secretion and in the intracellular concentration of free Ca is described. The inhibition is maximal within 3 min of the addition of PMA and is concentration-dependent (IC50 [median inhibitory concentration dose] = 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 Ca and the permeability changes to Ca induced by chemotactic factors, but does not affect the stimulation of the rate of influx of Na produced by the same agents. The PMA analog 4.alpha.-phorbol 12,13-didecanoate, which lacks tumorigenicity and the ability to activate the Ca- and phospholipid-dependent protein kinase (protein kinase C), does not inhibit any of the above formyl fMet-Leu-Phe-stimulated neutrophil functions. Apparently, phorbol esters, either directly or indirectly, possibly through the activation of protein kinase C, inhibit the signal(s) responsible for the stimulated mobilization of Ca in rabbit neutrophils.

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