Inhibitors of PI 3-kinase and MEK kinase differentially affect mediator secretion from immunologically activated human basophils

Effects of inhibitors of PI 3-kinase and MEK kinases were investigated on histamine, leukotriene C-4, (LTC4.), and cytokine release from human basophils stimulated with anti-IgE. The PI 3-kinase antagonists wortmannin (> 10 nM) and LY 294002 (>1 mu M) strongly inhibited anti-IgE-induced release of all mediators by 40-100%. This was contrasted by the effects of the MEK kinase inhibitor PD 098059, which weakly inhibited histamine, interleukin (IL)-4, and IL-13 release but was substantially more efficacious at blocking LTC4 production (>70% at 10 mu M). Previous studies have shown that arachidonic acid synthesis is controlled by MEK kinases. We observed that wortmannin, LY 294002, and PD 098059 reduce basophil ERK-1,2 activation, thus implying that, with regard to arachidonic acid metabolism, MEK kinases are a downstream target for PI-5-kinase. Our results demonstrate a universal regulatory role played by PI 3-kinases in basophil mediator production and release, whereas MEK kinase signaling is largely limited to controlling arachidonic acid metabolism.