MODULATION OF HUMAN NEUTROPHIL FUNCTION BY MONOHYDROXY-EICOSATETRAENOIC ACIDS

Abstract

The generation from arachidonic acid and purification of large quantities of a series of monohydroxy-eicosatetraenoic acids (HETE) which differed only in the position of the hydroxyl group permitted an in vitro analysis of the relative effects of the HETE on a variety of human neutrophil functions. All of the HETE elicited maximal neutrophil chemotactic responses of comparable magnitude, but the chemotactic potencies exhibited a distinct rank order with 5-HETE .mchgt. 8-HETE:9-HETE (85:15, wt:wt) > 11-HETE = 12-L-HETE. Peak chemotactic responses were achieved at concentrations of 1 .mu.g/ml for 5-HETE, 5 .mu.g/ml for 8-HETE:9-HETE and 10 .mu.g/ml for 11-HETE and 12-L-HETE. In the absence of a concentration gradient, the HETE were similar in potency with respect to the stimulation of neutrophil chemokinesis and the enhancement of the expression of neutrophil C3b [b fragment of complement component 3]-receptors. At optimally chemotactic and chemokinetic concentrations, none of the HETE stimulated the generation of superoxide by neutrophils, altered the expression of neutrophil Ig[immunoglobulin]G-Fc receptors or evoked the release of lysosomal enzymes. Methyl esterification of 5-HETE and 12-L-HETE reduced the chemotactic activity to less than 12% of that of the parent compound. The HETE methyl esters competitively inhibited the chemotactic activity of the homologous free acids by approximately 50% at equimolar concentrations, without inhibiting the chemotactic activity of formyl-methionyl peptides or of chemotactic fragments of C5fr. The stimulus specificity of the competitive inhibition of chemotaxis by HETE methyl esters and the functional selectivity of the HETE as compared to the formyl-methionyl peptides and C5fr, which stimulate neutrophil oxidative metabolism and lysosomal enzyme release, suggest that HETE activate human neutrophils by a unique mechanism.