The leukotriene B4 paradox: neutrophils can, but will not, respond to ligand-receptor interactions by forming leukotriene B4 or its ω-metabolites

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Abstract
Leukotriene B4 (5S,12R-dihydroxy-6,14-cis, 8,10-trans-eicosatetraenoic acid, LTB4) is released from neutrophils exposed to calcium ionophores. To determine whether LTB4 might be produced by ligand-receptor interactions at the plasmalemma, we treated human neutrophils with serum-treated zymosan (STZ), heat-aggregated IgG and fMet-Leu-Phe (fMLP), agonists at the C3b, Fc and fMLP receptors respectively. STZ (10 mg/ml) provoked the formation of barely detectable amounts of LTB4 (0.74 ng/107 cells); no .omega.-oxidized metabolites of LTB4 were found. Addition 10 .mu.M-arachidonate did not significantly increase production of LTB4 or its metabolites. Addition of 50 .mu.M-arachidonate (an amount which activates protein kinase C) before STZ caused a 40-fold increase in the quantity of LTB4 and its .omega.-oxidation products. Neither phorbol myristate acetate (PMA, 200 ng/ml) nor linoleic acid (50 .mu.M), also activators of protein kinase C, augmented generation of LTB4 by cells stimulated with STZ. Neither fMLP (10-6 M) nor aggregated IgG (0.3 mg/ml) induced LTB4 formation (< 0.01 ng/107 cells). Moreover, cells sexposed to STZ, fMLP, or IgG did not form all-trans-LTB4 or 5-hydroxyeicosatetraenoic acid; their failure to make LTB4 was therefore due to inactivity of neutrophil 5-lipoxygenase. However, adding 50 .mu.M-arachidonate to neutrophil suspensions before fMLP or IgG triggered LTB4 production, the majority of which was metablized to its .omega.-oxidized products (fMLP, 20.2 ng/107 cells; IgG, 17.1 ng/107 cells). The data show that neutrophils exposed to agonists at defined cell-surface receptors produce significant quantities of LTB4 only when treated with non-physiological concentrations of arachidonate.

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