THE ANTINEOPLASTIC BRYOSTATINS AFFECT HUMAN BASOPHILS AND MAST-CELLS DIFFERENTLY

Bryostatins, macrocyclic lactones from the marine bryozoan Bugula neri tina, are potent antineoplastic agents and multipotential stimulators of immune cells. We have examined the effects of bryostatins on mediat or release from human basophilic leukocytes and human tissue mast cell s. Bryostatins 1, 2, and 5 (10 to 3,000 nmol/L) induced histamine secr etion from purified and unpurified peripheral blood basophils, whereas they caused no release of peptide-leukotriene C-4 from these cells. T he rate of histamine release caused by bryostatin 1 was slower than th at caused by anti-IgE (t1/2 +/- SEM = 38.2 +/- 4.7 minutes v 8.9 +/- 0 .2 minutes; P < .01), whereas the temperature dependence was similar ( optimum release at 37 degrees C, approximately 30% less at 30 degrees C, and no release at 22 degrees C or 4 degrees C). The addition of inc reasing concentrations of extracellular Ca2+ to the medium caused hist amine release in the presence of bryostatins. Subeffective concentrati ons of bryostatins and anti-IgE produced a synergistic effect on hista mine release from basophils. Staurosporine, chelerythrine, and calphos tin C (0.1 to 10 nmol/L), which are protein kinase C inhibitors, inhib ited the histamine secretion activated by bryostatin 1 and tetradecano ylphorbol-acetate (TPA). Preincubation with granulocyte-monocyte colon y-stimulating factor (GM-CSF;1 and 5 nmol/L) and interleukin-3 (IL-3; 10 ng/mL) potentiated the activation of human basophils induced by bry ostatin 1. Neither bryostatin 1 nor bryostatin 2 induced the release o f histamine from mast cells isolated from human lung or skin tissues. However, brief (10 minutes) preincubation with bryostatin 1 (3 to 300 nmol/L) potently inhibited the histamine secretion induced by anti-IgE from skin or lung mast cells. Bryostatin 1 was a more potent (by appr oximately 30 times) inhibitor of IgE-mediated histamine release than w as TPA. The heterogeneous effects exerted by bryostatins on human baso phils and mast cells can be of interest for those designing therapeuti c trials using these agents. (C) 1995 by The American Society of Hemat ology.