Regulation of human leukocyte function by lipoxygenase products of arachidonic acid

Oxygenation of arachidonic acid via the 5- and 15-lipoxygenase pathways yields a variety of products, including monohydroxyeicosatetraenoic acids (HETEs) and more complex products termed leukotrienes. Of these products leukotriene B4 (LTB4) is the most potent modulator of PMN function. Nanomolar concentrations of LTB4 elicit PMN chemotaxis both in vitro and in vivo, and 3- to 10-fold higher concentrations of LTB4 promote lysosomal degranulation, PMN leukocyte aggregation, and adherence, in addition to enhancing the expression of neutrophil and eosinophil C3b receptors. The PMN-directed effects of LTB4 are mediated by binding to a distinct subset of PMN receptors. LTB4 is bound stereospecifically by 26,000-40,000 receptors per PMN, and the receptors have a KD of 10.8-13.9 nM. The receptor for LTB4 may also mediate PMN activation by other 5-lipoxygenase products, as the capacity of these products to activate PMN leukocyte function correlates with their capacity to compete with LTB4 for binding by the receptor. Several observations suggest that LTB4 may function both as an extracellular mediator of PMN function and as a critical intracellular intermediate in cellular activation by other agents. These observations include the localization of the LTB4 receptor in neutrophil granules, the dependence of PMN activation by different stimuli on the lipoxygenation of arachidonic acid, and the capacity of LTB4 to promote calcium flux in liposomes. Arachidonic acid oxygenation products have complex effects on T-lymphocyte function. LTB4 enhances T-lymphocyte chemokinesis and inhibits the generation of lymphokines and cellular transformation. LTC4 inhibits the generation of lymphokines without affecting transformation or chemokinesis. 5-HETE enhances and 15-HETE inhibits chemokinesis, whereas these products have no effects on the other lymphocyte functions. Thus, the lipoxygenase products of arachidonic acid are potent modulators of T-lymphocyte and PMN-function; these products may function both as extracellular mediators and as intracellular intermediates in cellular activation.