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 occurs during active secretion has also been associated with the methodological phenomenon called desensitization, but the mechanisms underlying desensitization are not understood. A variety of studies have suggested that activation of protein kinase C (PKC) results in down-regulation of IgE-mediated secretion 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 concentrations that have been shown previously to inhibit PKC-mediated functions in 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)pyrazolo[3, 4-d]pyrimidine] inhibited 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 dependent on the activation of src family kinases.
MacGlashan
D
D
Johns Hopkins Asthma and Allergy Center, 21224, USA, Baltimore, MD, USA. dmacglas@welch.jhu.edu
Miura
K
K
Lavens-Phillips
S
S
D001491:Basophils / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D002352:Carrier Proteins / Q000494:pharmacology; D003888:Desensitization, Immunologic; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006636:Histamine Release / Q000187:drug effects; D006801:Humans; D006969:Hypersensitivity, Immediate / Q000201:enzymology* / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins; D011233:Precipitin Tests; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
C108123:4-amino-5-(4-methylphenyl)-7-(tert-butyl)pyrazolo(3,4-d)pyrimidine; C412373:AG 1879; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D011720:Pyrazoles; D011743:Pyrimidines; C015482:protein kinase modulator; D011505:Protein-Tyrosine Kinases; D019061:src-Family Kinases; D011493:Protein Kinase C