Aspirin and salicylates modulate IgE-mediated leukotriene secretion in mast cells through a dihydropyridine receptor-mediated Ca2+ influx

Aspirin is a well-known nonsteroidal anti-inflammatory drug (NSAID) that may potentiate some acute allergies and causes adverse immunological reactions collectively referred to as aspirin intolerance. Aspirin intolerance is accompanied by increased leukotriene (LT) synthesis, and high levels of serum IgE are a risk factor for NSAID sensitivity. Here we demonstrate that aspirin modulates LTC4 secretion in mast cells. Therapeutic levels of aspirin and salicylates (≤ 0.3 mM, i.e., the concentrations observed in vivo in the use of antipyretic analgesic) increased IgE-mediated LTC4 secretion. Aspirin-induced stimulation was accompanied by increased Ser-505 phosphorylation of cytosolic phospholipase A2, which occurred independently of extracellular signal-regulated protein kinase-1/2 and p38 mitogen-activated protein kinase pathways. Aspirin also increased IgE-mediated Ca2+ influx, whereas aspirin at concentrations of ≥ 0.3 mM dose-dependently reduced Ca2+ store emptying and Ca2+ release-activated Ca2+ channel activation. Instead, aspirin facilitated a dihydropyridine receptor-mediated Ca2+ influx, resulting in increased LTC4 secretion. This novel action of aspirin may play roles in exacerbation of immediate allergy and aspirin intolerance.