Differential Effects of Lipoxygenase Products on FMLP and LTB4 Evoked Neutrophil Aggregation

There is evidence that the endogenous biosynthesis of LTB4 is involved in the aggregation of human neutrophils induced by the chemotactic peptide f-met-leu-phe (FMLP). If LTB4 mediates this aggregatory response, then agents which desensitize neutrophils to LTB4 should inhibit the cellular response to FMLP. Since many lipoxygenase products modulate other neutrophil responses to LTB4 and FMLP, we have investigated the effects of lipoxygenase products on LTB4- and FMLP-initiated aggregation. Prior exposure to low concentrations of LTB4 (0.5-10 nM) inhibited subsequent aggregation to the same agent (50 nM), but it did not influence the response to FMLP (10(-7) M). Relatively high concentrations of 5-HETE (5-50 microM) inhibited aggregation initiated by either stimulus. Although the hydroperoxy derivative 5-HPETE also inhibited the response to LTB4, in the relatively narrow concentration range of 1-4 microM it stimulated FMLP-induced aggregation. This latter effect was confirmed using 12 cell preparations from six separate donors; it (the activity of 5-HPETE) was not mimicked by other 5-lipoxygenase products, including LTB4, nor the dihydroperoxide 8,15-DiHPETE. Our results indicate that neutrophil aggregation in response to LTB4 or FMLP can be selectively potentiated or inhibited. On the basis of these data we conclude that the endogenous synthesis of LTB4 is not directly involved in the neutrophil aggregatory response to FMLP, although the hydroperoxy intermediate 5-HPETE may act to enhance the cellular response.