期刊
BLOOD
卷 111, 期 6, 页码 3097-3107出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2007-08-104372
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- Austrian Science Fund FWF [Y 163] Funding Source: Medline
Dasatinib is a multitargeted drug that blocks several tyrosine kinases. Apart from its well-known antileukemic activity, the drug has attracted attention because of potential immunosuppressive and anti-inflammatory effects. We report that dasatinib at 1 mu M completely blocks anti-IgE-induced histamine release in blood basophils in healthy donors, and allergen-induced release of histamine in sensitized individuals. In addition, dasatinib inhibited FC is an element of RI-mediated release of IL-4 and IgE-mediated up-regulation of CD13, CD63, CD164, and CD203c in basophils. The effects of dasatinib were dose-dependent (IC50: 50-500 nM) and specific for Fc is an element of RI activation in that the drug failed to inhibit C5a-induced or Ca-ionophore-induced histamine release. Interestingly, at lower concentrations, dasatinib even promoted Fc is an element of RI-dependent histamine release in basophils in allergic subjects. In consecutive studies, dasatinib was found to interact with and block several Fc is an element of RI downstream targets in basophils, including Btk. Correspondingly, Fc is an element of RI-mediated histamine secretion in basophils was markedly reduced in Btk knockout mice and in a patient with Btk deficiency. However, the remaining low-level mediator secretion in Btk-deficient cells was fully blocked down again by 1 mu M dasatinib. Together, these data suggest that dasatinib inhibits FC is an element of RI-mediated activation of basophils through multiple signaling molecules including Btk. Dasatinib may be an interesting agent for immunologic disorders involving Btk-dependent responses or/and FC is an element of RI activation of basophils.
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