lipoxin-b4 and Leukemia--Erythroblastic--Acute

Earlier studies in our laboratory suggested a role for 15-lipoxygenase products of arachidonic acid, such as 15-hydroperoxyeicosatetraenoic acid and 15-hydroxyeicosatetraenoic acid, in supporting proliferative events in Friend erythroleukemia cells. Because lipoxins are also products of the same lipoxygenase enzyme, we tested their actions on signal transduction events related to DNA synthesis. Lipoxins A4 and B4 (10 nM) significantly enhanced [3H]thymidine incorporation into Friend cells in the absence of fetal bovine serum without affecting cell differentiation or cell number. Lipoxin B4 increased the duration of time that cells spent in the S phase of the cell cycle, and also significantly enhanced protein kinase C activity in nuclei, whereas c-fos expression was unaffected by either of the lipoxins tested. The novel, intracellular actions of lipoxins A and B on Friend erythroleukemia cells documented in this study represent a unique spectrum of effects of lipoxins on signal transduction events as compared with other eicosanoids.

Topics: Animals; Cell Differentiation; Cell Division; Enzyme Activation; Friend murine leukemia virus; Gene Expression; Genes, fos; Hydroxyeicosatetraenoic Acids; Leukemia, Erythroblastic, Acute; Lipoxins; Protein Kinase C; Signal Transduction; Tumor Cells, Cultured

Lipoxin A (5,6,15L-trihydroxy-7,9,11,13-eicosatetraenoic acid) and lipoxin B (5D,14,15-trihydroxy-6,8,10,12-eicosatetraenoic acid), two newly isolated compounds derived from the oxygenation of arachidonic acid in human leukocytes, inhibit the cytotoxic activity of human natural killer (NK) cells. Dose-response studies showed that both lipoxin A and lipoxin B inhibit, at submicromolar concentrations (ID50 10(-7) M), NK cell activity assayed against K562 target cells. Prostaglandin E2 (PGE2) also inhibited cytotoxicity, whereas both 15-HETE (5(S)-hydroxy-5,8,11,13-eicosatetraenoic acid) and leukotriene B4 (synthetic and biologically derived) were ineffective. PGE2 stimulated a time- and dose-dependent increase in intracellular cAMP, which was accompanied by a decrease in NK target cell binding. Lipoxin A and lipoxin B did not elevate intracellular cAMP, nor did they inhibit target cell binding. Together these findings suggest that lipoxin A and lipoxin B abrogate NK cell cytotoxicity at a step distal to target effector cell recognition. In contrast, PGE2 appears to exert its effect, at least in part, on cytotoxicity indirectly by decreasing the binding between target and effector cells (in vitro). Moreover, they suggest that novel oxygenated derivatives of arachidonic acid (i.e., lipoxin A, lipoxin B) may regulate the activities of NK cells.

Topics: Binding Sites; Binding, Competitive; Cell Line; Cyclic AMP; Cytotoxicity, Immunologic; Dinoprostone; Humans; Hydroxyeicosatetraenoic Acids; Intracellular Fluid; Killer Cells, Natural; Leukemia, Erythroblastic, Acute; Lipoxins; Prostaglandins E