PHARMACOLOGICAL INVESTIGATIONS WITH DIFFERENT PROTEIN-KINASE-C INHIBITORS ON IGE-DEPENDENT AND IGE-INDEPENDENT ACTIVATION OF HUMAN BASOPHILS

In the present study different selective inhibitors of the multifunctional serine/threonine kinase protein kinase C (PKC) were investigated on classical activation pathways of basophils in comparison to the nonselective protein kinase inhibitor staurosporine. The potent inhibitors Ro 31-7549, Ro 31-8220, calphostin C and ilmofosine (BM 41.440), which show selectivity for PKC in vitro, significantly potentiated Fc(epsilon)RI-mediated histamine release up to 50% vs. controls at concentrations > 10(-7) mumol/l but were without any intrinsic histamine releasing activity. Direct activation of cellular PKC by phorbol ester was suppressed by all compounds apart from ilmofosine at the same concentrations. We did not observe statistically significant effects of selective PKC inhibitors on exocytosis induced by the peptide formyl-meth-leu-phe (FMLP) or the ionophore A23187, whereas staurosporine potentiated the FMLP-induced histamine release in a dose-dependent fashion: maximum potentiation was 63.5 +/- 8.9% vs. control at 1 mumol/l (n = 4). The findings suggest that PKC exhibits differential functions during biochemical events of stimulus-secretion coupling in human basophils supposedly by its distinct subtypes. With respect to the present data, TPA-induced and IgE-mediated signals are not closely correlated.