6-ketoprostaglandin-f1-alpha and 13-hydroxy-9-11-octadecadienoic-acid

The effects of several inhibitors of lipoxygenases were investigated in murine spleen cell cultures activated with endotoxin (lipopolysaccharide). It was found that these inhibitors interfere with the proliferative response of the cultures. Indomethacin, a specific cyclooxygenase inhibitor, had no such effect. Endotoxin induced the synthesis of tumour necrosis factor alpha in spleen cells which was prevented by treatment with a lipoxygenase inhibitor. The inhibition of the mitogenic effect of endotoxin could be reversed by addition of 13-hydroxyoctadecadienoic acid. This was not the case with leukotriene B4 and C4 or 15-hydroxyeicosatetraenoic acid. In contrast, these substances had inhibitory effects on the mitogenicity of spleen cells. It is suggested that 13-hydroxyoctadecadienoic acid is involved in the development of the mitogenic reaction, possibly on the level of tumour necrosis factor alpha production of macrophages present in the cultures.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Antithrombins; Bacterial Toxins; Cell Division; Cell Survival; Cells, Cultured; Dose-Response Relationship, Drug; Endotoxins; Enterotoxins; Female; Linoleic Acids; Lipopolysaccharides; Lipoxygenase Inhibitors; Lymphocyte Activation; Macrophages; Mice; Mice, Inbred BALB C; Salmonella; Spleen; SRS-A; Tumor Necrosis Factor-alpha

Adhesion of tumor cells to vascular endothelial surfaces is one of the key steps in metastatic dissemination. Several factors are believed to be implicated in the regulation of the adhesive properties of tumor cells. We show that the adhesion of five different tumor cell lines, all of them of human origin, to human umbilical vascular endothelial cells (ECs) significantly increases following pretreatment of ECs with the cytokines interleukin-1 and tumor necrosis factor, whereas tumor cell/EC interactions remained unchanged after incubation with interferon-gamma. Significant augmentation in tumor cell adhesion was also observed when ECs were treated with the lipoxygenase inhibitors salicylate and the compound BW755C. In all cases, increased tumor cell adhesion was concomitant with significant decreases in the EC levels of linoleic acid, lipoxygenase-derived metabolite 13-hydroxy-octadecadienoic acid (13-HODE). On the contrary, pretreatment of the EC monolayers with aspirin did not result in any changes towards tumor cell adhesion. These results suggest that tumor cell/EC interaction is modulated, at least in part, by intracellular levels of 13-HODE and is independent of prostacyclin (PGI2) production by the ECs.

Topics: 6-Ketoprostaglandin F1 alpha; Cell Adhesion; Endothelium, Vascular; Epoprostenol; Humans; Interferon-gamma; Interleukin-1; Linoleic Acids; Neoplasm Invasiveness; Recombinant Proteins; Tumor Necrosis Factor-alpha

The effect of 13-hydroxyoctadecadienoic acid (13-HODE), an endogenous lipoxygenase metabolite of linoleic acid, on prostacyclin production by fetal bovine aortic endothelial cells was evaluated. Time-dependent release of radioimmunoassayable 6KPGF1 alpha in the presence of 13-HODE (10 uM) was stimulated by 39%, 27%, and 34% at 10, 30 and 120 min respectively. 13-HODE (10 uM) had no effect on the conversion of exogenous [14C] arachidonic acid (AA) to prostacyclin. When the effect on AA release was evaluated in [14C] AA prelabeled cells, 13-HODE (10nM) stimulated the release of AA from membrane phospholipids. Analysis of cellular phospholipids revealed a significant decrease in phosphatidylethanolamine. Our results demonstrate that 13-HODE stimulates prostacyclin production by enhancing AA release from phospholipids.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Arachidonic Acids; Cattle; Cells, Cultured; Chromatography, High Pressure Liquid; Endothelium; Epoprostenol; Linoleic Acid; Linoleic Acids; Lipoxygenase; Membrane Lipids; Phospholipids