TY - JOUR
T1 - Pharmacology of IgE-mediated desensitization of human basophils
T2 - Effects of protein kinase C and Src-family kinase inhibitors
AU - MacGlashan, Donald
AU - Miura, Katsushi
AU - Lavens-Phillips, Sandra
N1 - Funding Information:
These studies were supported by NIH Grant AI20253.
PY - 2000/12/1
Y1 - 2000/12/1
N2 - 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. (C) 2000 Elsevier Science Inc.
AB - 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. (C) 2000 Elsevier Science Inc.
KW - Desensitization
KW - Histamine release
KW - Human basophils
KW - Protein kinase C
KW - Src kinases
KW - Syk kinase
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U2 - 10.1016/S0006-2952(00)00490-1
DO - 10.1016/S0006-2952(00)00490-1
M3 - Article
C2 - 11077055
AN - SCOPUS:0034578527
SN - 0006-2952
VL - 60
SP - 1717
EP - 1727
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
IS - 11
ER -