CGP-41251, A NOVEL PROTEIN-KINASE INHIBITOR WITH IN-VITRO SELECTIVITYFOR PROTEIN-KINASE-C, STRONGLY INHIBITS IMMUNOLOGICAL ACTIVATION OF HUMAN SKIN MAST-CELLS AND HUMAN BASOPHILS

The process of high-affinity IgE receptor (Fc(epsilon)RI)-mediated sig nal transduction in human basophils and mast cells is accompanied by a ctivation of protein kinase C (PKC). The present study investigated th e effects of a novel protein kinase inhibitor with in vitro selectivit y for PKC (CGP 41251) in comparison with the potent but non-selective PKC inhibitor staurosporine on the activation of human peripheral baso philic leukocytes and enzymatically isolated human skin mast cells. CG P 41251 exerted strong concentration-dependent inhibitory effects on F c(epsilon)RI-mediated histamine release from both cell populations. In addition, the IgE-mediated generation of arachidonic acid metabolites (leukotriene C4/D4 and prostaglandin E2) from human basophils was als o significantly inhibited by this compound. Its action was not signifi cantly different from the action of staurosporine. Direct activation o f cellular PKC by the phorbol ester 12-o-tetradecanoyl-phorbol-13-acet ate and subsequent histamine release from basophils was also inhibited by both compounds. CGP 41251 did not suppress N-formyl-met-leu-phe-or A23187-induced activation of basophils, whereas A23187-induced mediat or release from human skin mast cells was inhibited in a concentration -dependent fashion. We conclude that an increase of in vitro selectivi ty for PKC does not significantly enhance inhibitory effects on immuno logical activation of histamine-containing cells. Moreover, nonimmunol ogical pathways of signal transduction in basophils and mast cells app ear to be mediated by distinct biochemical events.