Diverse lipid products of arachidonic acid were examined for in vitro human polymorphonuclear (PMN) leukocyte chemotactic activity and the ability to enhance PMN leukocyte migration in the absence of a concentration gradient of the stimulus, an effect termed chemokinesis. Highly purified 12-L-hydroxy-5,8,10-eicosatetraenoic acid (HETE), a lipoxygenase product, and 12-L-hydroxy-5,8,10-heptadecatrienoic acid (HHT), a cyclo-oxygenase product, were chemotactic for PMN leukocytes in concentrations ranging from 0.7 to 25 µg/ml and 2 to 50 µg/ml, respectively, with a preference for the eosinophil series. Preincubation with peak chemotactic concentrations of either hydroxy-lipid product irreversibly suppressed the response of PMN leukocytes to the homologous and other chemotactic stimuli. At minimally chemotactic concentrations, both HETE and HHT were positively chemokinetic and enhanced the chemotactic response of PMN leukocytes to the homologous lipid and to a stimulus derived from human C5 by tryptic digestion. PGE2 and PGF2α lacked chemotactic activity, but exhibited negative and positive chemokinetic activity, respectively, whereas thromboxane B2 had no effect on PMN leukocyte migration. Thus, HHT is the first leukocyte chemotactic factor that is a product of the cyclooxygenase pathway and whose generation would thus be inhibited by nonsteroidal anti-inflammatory agents. Unlike the potently deactivating chemotactic factors, such as the tetrapeptides of the eosinophil chemotactic factor of anaphylaxis (ECF-A), HHT and HETE are chemokinetic at low concentrations and may enhance PMN leukocyte influx in response to other chemotactic stimuli.
This work was supported in part by Grant HL-19777 from the National Institutes of Health, Bethesda, Maryland.