15-hydroxy-5-8-11-13-eicosatetraenoic-acid and Lymphoma

In the BW5147 T cell line, we have identified two independent regulatory pathways by which arachidonic acid (20:4) can alter gene expression. The inhibitory effect of 20:4 upon stearoyl-CoA desaturase 2 (SCD2) gene expression was seen to be independent of oxidation of 20:4 by either the lipoxygenase or cyclooxygenase pathways. Moreover, oxidized metabolites of 20:4 (15-HPETE and 15-HETE) failed to diminish SCD2 mRNA accumulation whereas 20:4 itself was effective in completely suppressing SCD2 gene expression. In contrast, the transcriptional induction of the proto-oncogene c-fos was dependent upon the oxidation of 20:4 by the lipoxygenase pathway. By using the protein synthesis inhibitor, cycloheximide, we also show that the 20:4-mediated regulatory effects upon SCD2 or c-fos are completely independent of new protein synthesis. Collectively, the results identify the existence of multiple, independent, intracellular 20:4-mediated regulatory pathways operating simultaneously within this cell type.

Topics: Actins; Animals; Arachidonic Acid; Blotting, Northern; Cell Nucleus; Cycloheximide; Ethanol; Gene Expression; Gene Expression Regulation, Neoplastic; Genes, fos; Genes, jun; Hydroxyeicosatetraenoic Acids; Leukotrienes; Lipid Peroxides; Lymphoma; Masoprocol; Mice; RNA, Messenger; RNA, Neoplasm; Stearoyl-CoA Desaturase; T-Lymphocytes; Tetradecanoylphorbol Acetate; Transcription, Genetic; Tumor Cells, Cultured

Several investigations have suggested that products of arachidonic acid metabolism have modulatory effects on the development of cellular immunity. In this report we have studied the role of arachidonic acid metabolism in the specific effects of interleukin 1 (IL 1) induction of interleukin 2 (IL 2), and also IL 2 stimulation of proliferation and interferon-gamma (IFN-gamma) production. Utilizing cell lines that are specifically responsive to IL 1 or IL 2, it was found that both interleukins stimulate lipoxygenation of arachidonic acid in their respective target cell. The ability of each interleukin to induce monohydroxyeicosatetraenoic acid (HETE) correlated with the induction of secondary lymphokine secretion. Utilizing selective and partially selective pharmacologic inhibitors of arachidonic acid metabolism, the data suggest that the participation of lipoxygenase activity is required for both IL 1 induction of IL 2 production and IL 2 regulation of proliferation and IFN-gamma secretion. The same requirement for lipoxygenase activity was seen when phorbol myristate acetate (PMA) was used as a secretory stimulant, suggesting a similar mode of action for stimulation-secretory activity between PMA and interleukins. Studies performed with an endogenous inhibitor of 5-lipoxygenase (15-HETE) demonstrated the requirement of this enzyme system for IL 2-dependent proliferation and IFN-gamma production. Although leukotrienes could replace IL 2 for IFN-gamma secretion, they had no effect on IL 2 growth promotion. The results suggest that both IL 1 and IL 2, and PMA, may share the lipoxygenase pathway of arachidonic acid metabolism which is a component of the intracellular signal transduction process that regulates secretory activity and/or cellular proliferation.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Cell Line; Humans; Hydroxyeicosatetraenoic Acids; Indomethacin; Interleukin-1; Interleukin-2; Lipoxygenase; Lymphocyte Activation; Lymphoma; Mice; T-Lymphocytes