ROLE OF 5'-LIPOXYGENASE METABOLITES IN THE ACTIVATION OF PERITONEAL-MACROPHAGES FOR TUMORICIDAL FUNCTION

Metabolites of arachidonic acid have been shown to be potent biological modulators of macrophage function. While the role of cyclooxygenase metabolites of arachidonic acid have been well studied, metabolites of lipoxygenase have not. In this report, we evaluate the role that select 5'-lipoxygenase (5'-LO) products may play in macrophage activation for select tumoricidal functions. When thioglycollate-elicited macrophages were treated with inhibitors of 5'-LO during activation, cytolytic capacity, nitric oxide production, and tumor necrosis factor-cu production were significantly inhibited. Moreover, both an inhibitor of the 5'-LO-activating protein and an inhibitor of glutathione-s-transferase (GST) significantly decreased macrophage tumoricidal function. The activating agents used were able to stimulate 5'-LO activity which was measured by quantitating secreted LTC(4). Increased production of PGE(2) by shunting could have been the cause for decreased macrophage tumoricidal function. However, treatment of macrophages with inhibitors of 5'-LO during lipopolysaccharide stimulation did not increase formation of PGE(2). When select 5'-LO metabolites were added to cultures during activation and 5'-LO inhibition, tumoricidal activity could not be restored, even when the metabolites were encapsulated in liposomes, These results suggest that the activity of 5'-LO and GST are important for macrophage activation. However, the specific role of 5'-LO metabolites has not been completely established. (C) 1995 Academic Press, Inc.