PHARMACOLOGICAL STUDY OF BASOPHIL HISTAMINE-RELEASE INDUCED BY MONOCYTE CHEMOTACTIC PROTEIN-1 WITH KINASE INHIBITORS

Monocyte chemotactic protein-1 (MCP-l)/monocyte chemotactic activating factor has a potent histamine-releasing activity for basophils and is a major component of IgE-independent histamine-releasing factors (HRF ). In this study, we examined the effect of a panel of kinase inhibito rs on MCP-l-induced histamine release from human basophils to characte rize the signaling pathway used by this chemokine. Genistein (3 mu g/m l), an inhibitor of tyrosine kinase, inhibited MCP-l-induced histamine release by 44%. Wortmannin is a specific inhibitor of phosphatidylino sitol 3 kinase (PI-3 kinase). It blocked MCP-l-induced histamine relea se with an IC50 of 3.3 x 10(-8) M indicating a role of PI-3 kinase in this reaction. KT5926, an inhibitor of myosin light chain kinase, also inhibited histamine release in response to MCP-1 with an IC50 of 10(- 6) M, Staurosporine, a potent inhibitor of protein kinase C, although being not specific, augmented MCP-1-induced histamine release by 31.9% at 10(-6) M. These results indicate the possible involvement of a ser ies of kinases, including PI-3 kinase, in the signal transduction path way used by MCP-1.