Effects of Arachidonic Acid and Its Metabolites on Antigen-Induced Histamine Release from Human Basophils in Vitro

Abstract

Abstract We have studied the role of arachidonic acid (AA) metabolism in immediate hypersensitivity reactions. The AA analog, eicosa-5,8,11,14-tetraynoic acid (ETYA), which inhibits both the cyclo-oxygenase and lipoxygenase pathways of AA metabolism, was found to cause a dose-dependent inhibition of antigen-induced histamine release from human basophils; complete inhibition occurred at 10-4 M. In contrast, nonsteroidal anti-inflammatory drugs (NSAID) including indomethacin (10-9 to 10-6 M), meclofenamic acid (10-6 to 10-4 M), and aspirin (10-5 to 10-3 M), which block the cyclo-oxygenase pathway of AA metabolism, enhanced mediator release. AA (10-7 to 10-5 M) also enhanced basophil mediator release, an effect that was not affected by preincubation with indomethacin. Other fatty acids including linoleic, linolenic, and stearic acids were without effect. Indomethacin (and the other NSAID studied) reversed the inhibition caused by the AA metabolite, prostaglandin (PG) E2, in a dose-dependent fashion. This reversal of inhibition was not unique to PG, but was observed with all inhibitors of histamine release studied that act via activation of adenylate cyclase including isoproterenol and the H2 agonist, dimaprit. NSAID, however, did not reverse the inhibition caused by drugs that do not act on adenylate cyclase, i.e., dibutyryl cAMP, isobutylmethylxanthine, and 2-deoxyglucose. In the leukocyte preparations studied, the NSAID did not block the increase in the intracellular cAMP levels caused by agonists that act via adenylate cyclase. It appears that a product(s) of AA metabolism, generated via the lipoxygenase pathway, is involved in IgE-mediated histamine release and that the same or a different product(s) modulates the control mechanisms that are linked to adenylate cyclase.