LIPOXYGENASE PRODUCTS REGULATE PROLIFERATION OF GRANULOCYTE-MACROPHAGE PROGENITORS

We studied the role of lipoxygenase products on the proliferation and recovery of granulocyte-macrophage progenitors (CFU-GM) in liquid cult ures of normal human blood mononuclear cells containing physiologic or slightly higher than physiologic concentrations of hydrocortisone (HC ). Lipoxygenase blockade by addition of nordihydroguaiaretic acid (NDG A) resulted in enhanced recovery of CFU-GM (mean increase of 230%). Th e number of CFU-GM recovered from 14-day liquid cultures containing 1. 0 mu M HC plus 10 mu M NDGA was a mean of six times higher than the nu mber present in the inoculum. Effects of addition of selected 5-lipoxy genase products into the cultures containing a lipoxygenase blocker on the CFU-GM recovery and proliferative activity were dose- and metabol ite-specific. Leukotriene (LT) Bq and 5-hydroxy-eicosatetraenoic acid (5-HETE) decreased recovery of CFU-GM while LTC(4) and LTD(4) had biph asic effects-lower doses decreased while higher doses had no effect on CFU-GM recovery. Lipoxygenase blockade decreased the percent of CFU-G M in DNA synthesis phase. Readdition of LTB(4) did not reverse this ef fect while LTD(4) had a biphasic effect-low concentrations increased t he percent of CFU-GM in DNA synthesis phase to levels equivalent to CF U-GM in cultures without NDGA while higher concentrations had no effec t. In semisolid CFU-GM assays, lipoxygenase blockade with NDGA complet ely prevented CFU-GM colony formation, suggesting that NDGA inhibits p roliferation and/or differentiation of CFU-GM in semisolid culture ass ays. The results of our studies suggest that 5-lipoxygenase metabolite s are physiologically important in regulating the proliferation of CFU -GM and, thus, granulopoiesis.