Inhibition of leukotriene biosynthesis by the leukocyte product 15-hydroxy-5,8,11,13-eicosatetraenoic acid

Abstract

Rabbit peritoneal polymorphonuclear leukocytes, elicited with glycogen, metabolized added [1-14C]arachidonic acid to the 5-lipoxygenase products 5-hydroxy-6,8,11,14-eicosatetraenoic acid and 5,12-dihydroxy-6,8,10,14-eicosatetraenoic acid (leukotriene B) and the 15-lipoxygenase product 15-hydroxy-5,8,11,13-eicosatetraenoic acid. These metabolites were isolated by high pressure liquid chromatography and converted to the trimethylsilyl-ether methyl ester derivatives, and the structures were confirmed by gas chromatography-mass spectrometry. When polymorphonuclear leukocytes were preincubated with 15-HETE (16 microM), the formation of 5-hydroxy-6,8,11,14-eicosatetraenoic acid and 5,12-dihydroxy-6,8,10,14-eicostatetraenoic acid from [1-14C]arachidonic acid was strongly suppressed. The concentration required for 50% inhibition of the 5-lipoxygenase pathway in these cells was approximately 6 microM, which is comparable to the concentrations (0.20 to 1.8 microM) of 15-hydroxy-5,8,11,13-eicosatetraenoic acid produced in incubations of polymorphonuclear leukocytes with arachidonic acid alone. Recent reports indicate that slow-reacting substance of anaphylaxis (leukotriene C/D) and chemotactic substance leukotriene B are arachidonic acid metabolites formed via the 5-lipoxygenase pathway. Our observations thus suggest that 15-hydroxy-5,8,11,13-eicosatetraenoic acid can regulate the formation of these vasoactive and inflammatory mediators intracellularly.