Pharmacology of IgE-mediated desensitization of human basophils: Effects of protein kinase C and Src-family kinase inhibitors

IgE-mediated down-regulation of secretion from basophils and mast cells is an important component of the overall cellular response that determines the ultimate extent of mediator release. The down-regulatory process that occu rs during active secretion has also been associated with the methodological phenomenon called desensitization, but the mechanisms underlying desensiti zation are not understood. A variety of studies have suggested that activat ion of protein kinase C (PKC) results in down-regulation of IgE-mediated se cretion so we have examined the effect of the PKC inhibitors Ro-31-8220 (3- [1-[3-amidinothio)propyl-1H-indol-3-yl]-3-(1-methyl-1H-indol-3-yl)maleimide ) and bis-indolylmaleimide II on desensitization in human basophils. At con centrations that have been shown previously to inhibit PKC-mediated functio ns iii basophils completely, these two drugs had no effect on]IgE-mediated desensitization We did find, however, that the src-family kinase inhibitors PP1 [ 4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine] and PP2 [4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazola[3,4-d]pyrimidine] inhi bited desensitization as well as secretion. These data suggest that PKC has little role in down-regulating the IgE-mediated basophil response. However , like the activation signaling cascade, the desensitization process is dep endent on the activation of src family kinases. (C) 2000 Elsevier Science I nc.