LIPOXIN-A(4) METABOLISM BY DIFFERENTIATED HL-60 CELLS AND HUMAN MONOCYTES - CONVERSION TO NOVEL 15-OXO AND DIHYDRO PRODUCTS

Lipoxins are tetraene-containing eicosanoids that possess biological a ctivity in several organ systems. To determine their route of further metabolism, [11,12-H-3]lipoxin A4 was prepared and incubated with huma n neutrophils, promyelocytic leukemia (HL-60) cells, and adherent mono cytes. Intact neutrophils and undifferentiated HL-60 cells did not sig nificantly metabolize [11,12-H-3]LXA4, while HL-60 cells differentiate d with PMA to monocyte/macrophage lineage rapidly (<15 s) transformed this eicosanoid. The major radiolabeled LXA4-derived metabolites were characterized by physical methods and were shown to be 15-oxo-LXA4, 13 ,14-dihydro-15-oxo-LXA4, and 13,14-dihydro-LXA4. Substrate competition with cell-free supernatants from differentiated HL-60 cells suggests that lipoxins compete for 15-hydroxyprostaglandin dehydrogenase activi ty or an equivalent enzyme system. In addition, adherent monocytes exp osed to [11,12-H-3]LXA4 rapidly metabolized (>60% within 30 s) the lab el to its oxo and dihydro derivatives. These results indicate that, un like leukotrienes, LXA4 is subject to dehydrogenation and reduction of its conjugated tetraene to form triene-containing products. Moreover, they suggest that monocytes participate in lipoxin metabolism in thei r local milieu.