Role of Tyrosine Kinases in IgE-mediated Signal Transduction in Human Lung Mast Cells and Basophils

Recent evidence suggests that tyrosine kinases play an important role in signal transduction mechanisms utilized by a range of different agonists in many cell types. We have investigated the effects of four different inhibitors of tyrosine kinases on IgE-dependent histamine release from human lung mast cells and basophils. Genistein inhibited the anti-IgE-induced histamine release from human basophils (at 10 µM genistein, inhibition = 55 ± 5%, n = 17, P < 0.005) with an IC50 of 8 µM, but was much less effective in the human lung mast cell (at 10 µM, inhibition = 18 ± 6%, n = 11, P < 0.05). Two inactive analogs of genistein, genistin and diadzein, failed to affect anti-IgE-induced histamine release significantly in either mast cells or basophils. A second inhibitor of tyrosine kinases, tyrphostin 25, inhibited IgE-dependent release from basophils (at 10 µM, inhibition = 25 ± 7%, n = 6, P < 0.05) though it was less effective than genistein and failed to affect IgE-induced histamine release from human lung mast cells (at 10 µM, inhibition = 22 ± 16%, n = 5, P = NS). In contrast, methyl 2,5 dihydroxycinnamate (MDC) failed to inhibit anti-IgE-dependent histamine release in human basophils (at 10 µM, inhibition = 3 ± 3%, n = 5, P = NS) but proved to be an effective inhibitor of anti-IgE-induced degranulation in human lung mast cells (at 10 µM, inhibition = 53 ± 16%, n = 5, P < 0.05). Finally, a fourth drug, lavendustin A, failed to inhibit histamine release from either basophils or lung mast cells. The ability of the drugs to affect histamine release in the different cell types did not appear to reflect their reported activity as inhibitors of epidermal growth factor receptor autophosphorylation or their putative sites of action on the enzyme. Genistein did not appear to be inhibiting protein kinase C as it failed to affect the release of histamine in basophils challenged with 10 ng/ml phorbol myristate acetate (at 10 µM, inhibition = 7 ± 4%, n = 5, P = NS). The differences between basophils and mast cells could not simply be ascribed to the different concentrations of anti-IgE used to initiate release as the inhibition caused by 10 µM genistein in both cell types was independent of the concentration of anti-IgE used and the net release of histamine. The efficacy and potency of genistein and lavendustin A in human basophils were not altered by increasing the pre-incubation period to 2 h. In summary, inhibitors of tyrosine kinases inhibit IgE-dependent histamine release from both human lung mast cells and basophils, though these two cell types exhibit distinct inhibitory profiles, possibly reflecting differences in IgE-dependent signal transduction mechanisms in these two cell types.