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Johns Hopkins Asthma and Allergy Center, Baltimore, MD 21224
Human basophils secrete histamine and leukotriene C4
(LTC4) in response to various stimuli, such as Ag and the
bacterial product, FMLP. IgE-mediated stimulation 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 IgE- and
FMLP-mediated stimulation of human basophils was examined. Following
FMLP stimulation, histamine release preceded phosphorylation of ERKs,
whereas phosphorylation of cytosolic phospholipase A2
(cPLA2), and arachidonic acid (AA) and LTC4
release followed phosphorylation of ERKs. The phosphorylation of ERKs
was transient, decreasing to baseline levels after 15 min. PD98059 (MEK
inhibitor) inhibited the phosphorylation of ERKs and cPLA2
without inhibition of several other tyrosine phosphorylation events,
including phosphorylation of p38 MAPK. PD98059 also inhibited
LTC4 generation (IC50 = 
2 µM), but not
histamine release. Stimulation with anti-IgE Ab resulted in the
phosphorylation of ERKs, which was kinetically similar to both
histamine and LTC4 release and decreased toward resting
levels by 30 min. Similar to FMLP, PD98059 inhibited
anti-IgE-mediated LTC4 release (IC50, 2
µM), with only a modest effect on histamine release and IL-4
production at higher concentrations. Taken together, these results
suggest that ERKs might selectively regulate the pathway leading to
LTC4 generation by phosphorylating cPLA2, but
not histamine release or IL-4 production, in human
basophils.
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