Extracellular signal-regulated kinases regulate leukotriene C4 generation,but not histamine release or IL-4 production from human basophils

Human basophils secrete histamine and leukotriene C4 (LTC4) in response to various stimuli, such as Ag and the bacterial product, FMLP. IgE-mediated s timulation also results in IL-4 secretion. However, the mechanisms of these three classes of secretion are unknown in human basophils, The activation of extracellular signal-regulated kinases (ERKs; ERK-1 and ERK-2) during Ig E- and EMLP-mediated stimulation of human basophils was examined. Following FMLP stimulation, histamine release preceded phosphorylation of ERKs, wher eas phosphorylation of cytosolic phospholipase A2 (cPLA(2)), and arachidoni c acid (AA) and LTC, release followed phosphorylation of ERKs. The phosphor ylation of ERKs was transient, decreasing to baseline levels after 15 min. PD98059 (MEK inhibitor) inhibited the phosphorylation of ERKs and cPLA(2) w ithout inhibition of several other tyrosine phosphorylation events, includi ng phosphorylation of p38 MAPK. PD98059 also inhibited LTC, generation (IC5 0 = similar to 2 mu M), but not histamine release. Stimulation with anti-Ig E Ab resulted in the phosphorylation of ERKs, which was kinetically similar to both histamine and LTC, release and decreased toward resting levels by 30 min. Similar to FMLP, PD98059 inhibited anti-IgE-mediated LTC4 release ( IC50, similar to 2 mu M), with only a modest effect on histamine release an d IL-4 production at higher concentrations. Taken together, these results s uggest that ERKs might selectively regulate the pathway leading to LTC, gen eration by phosphorylating cPLA(2), but not histamine release or IL-4 produ ction, in human basophils.