Inhibition of basophil histamine release by tyrosine kinase and phosphatidylinositol 3-kinase inhibitors

It has been demonstrated that tyrosine kinase (TK) and phosphatidylinositol 3-kinase (PI3-K) are involved in IgE-mediated stimulation of human basophi ls; conversely, little is known about the biochemical pathways activated by IL-3 and GM-CSF. The aim of this study was to evaluate the effects of TK a nd PI3-K inhibitors on basophil histamine release induced by anti-IgE, IL-3 and GM-CSF. Since IL-3 and GM-CSF cause histamine release from normal huma n basophils only when the inhibitory effect of extracellular Na+ has been r emoved, peripheral blood leukocytes were suspended in isotonic solutions co ntaining either 140 mM NaCl or 140 mM N-methyl-D-glucamine(+). After stimul ation with anti-IgE, IL-3 or GM-CSF, histamine release was measured by an a utomated fluorometric method. The effects of preincubation with four differ ent TK inhibitors (AG-126. genistein, lavendustin A, tyrphostin 51) and one PI3-K inhibitor (wortmannin) were evaluated. AG-126, genistein and lavendu stin A exerted a significant dose-dependent inhibitory effect on basophil h istamine release induced by anti-IgE (either in high or in low Na+ medium), IL-3 and GM-CSF. Among the TK inhibitors, lavendustin A exerted the most p otent activity, Followed by AG-126 and genistein. Tyrphostin 51 caused a we ak inhibition of histamine release induced by IL-3, GM-CSF and anti-IgE in a low Na+ medium, but not in a physiological Nai-containing medium. The PI3 -K inhibitor wortmannin exerted the most effective inhibitory activity on t he histamine release induced by the three agonists. The combined effects of lavendustin A and wortmannin were less than additive, suggesting that TK a nd PI3-K are involved in the same activation pathway in human basophils. Th ese results suggest a possible role of TK and P13-K in basophil histamine r elease induced by anti-IgE, IL-3 and GM-CSF. TK and PI3-K are indeed potent ial therapeutic targets for antiallergic drugs. (C) 2000 International Soci ety for Immunopharmacology. Published by Elsevier Science Ltd. All rights r eserved.