Release of histamine from human leukocytes stimulated with the tumor-promoting phorbol diesters. I. Characterization of the response

R. P. Schleimer, E. Gillespie, L. M. Lichtenstein

Research output: Contribution to journalArticlepeer-review

80 Scopus citations

Abstract

The tumor promotor and irritant, 12-O-tetradecanoyl-phorbol-13-acetate (TPA) has been found to release histamine from human leukocyte preparations. TPA (100 ng/ml) released from 40 to 80% of the total histamine from the cells of 14 different donors during a 45-min incubation. Other phorbol diesters released histamine but were less potent than TPA (TPA > PDD > PDBz > PDA > mTPA). The histamine-releasing astivity of the phorbol diesters correlated very closely not only with binding to a specific receptor in chicken embryo fibroblasts (r= 0.985), but also with their biologic activity in other systems. The rate of TPA-induced histamine release was slower than that of anti-IgE, whereas the temperature dependence was similar (optimum release 37°C, 50% decrease at 30°C, no release below 22°C or after a 30-min preincubation at 47°C). TPA caused histamine release in the absence of extracellular calcium, although the addition of calcium to the medium augmented the release. Release was not inhibited by 3 mM dibutyryl cyclic AMP, which did inhibit anti-IgE-induced release. Both TPA- and anti-IgE-induced release were inhibited by 2-deoxyglucose. Three known inhibitors of arachidonic acid metabolism, phenidone, 5,8,11,14-eicosatetraynoic acid, and 5,8,11-eicosatriynoic acid inhibited TPA-induced histamine release. The phospholipase inhibitor, bromphenacyl bromide, was also an effective inhibitor of TPA-induced histamine release. These findings suggest that the phorbol diesters are a unique class of histamine-releasing compounds that share with IgE-mediated stimuli some pathways in lipid metabolism but that are not regulated by cyclic AMP. the identification by others of a phorbol diester receptor, and the findings here that phorbol diesters cause histamine release suggest that the release of mediators important in allergic disease may occur by as yet undiscovered mechanisms operative in vivo.

Original languageEnglish (US)
Pages (from-to)570-574
Number of pages5
JournalJournal of Immunology
Volume126
Issue number2
StatePublished - Jan 1 1981

ASJC Scopus subject areas

  • Immunology

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