Inhibition of lymphocyte mitogenesis by an arachidonic acid hydroperoxide.
Incubation of murine spleen cells with the oxidation product of soybean lipoxidase-treated arachidonic acid results in profound inhibition of induction of proliferation and maturation of these cells. The active entity was shown to be the 15-hydroperoxide of arachidonic acid (15-HPAA). Inhibition of the enzymes of the cyclo-oxygenase pathway fails to disturb this effect, indicating that 15-HPAA is not a substrate for this series of enzymes. 15-HPAA produced in this manner interfered with RNA synthesis, DNA synthesis, and blastogenesis, while failing to exert cytotoxic effects on the cells themselves. A variety of lymphocyte subpopulations, distinguished by their responsiveness to a diverse group of mitogens, were all equally inhibited by the addition of 15-HPAA to culture. Addition of this agent even as late as 24 h after initiation of culture resulted in profound inhibition of the proliferative and differentiative responses of splenic B cells to bacterial lipopolysaccharide (LPS). Exposure of cells to 15-HPAA for 10-30 min was adequate to initiate inhibition, an event that exhibited marked temperature dependence. The effects of pre-incubation with 15-HPAA could not be reversed in its absence in recovery periods of up to 6 h prior to addition of LPS. The implications of these data with reference to cellular activation mechanisms are discussed.
D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology*; D002478:Cells, Cultured; D007213:Indomethacin / Q000494:pharmacology; D007700:Kinetics; D015289:Leukotrienes; D008054:Lipid Peroxides; D008213:Lymphocyte Activation / Q000187:drug effects*; D008214:Lymphocytes / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008934:Mitogens; D010545:Peroxides / Q000494:pharmacology*; D012313:RNA / Q000096:biosynthesis; D013696:Temperature
D001095:Arachidonic Acids; D015289:Leukotrienes; D008054:Lipid Peroxides; D008934:Mitogens; D010545:Peroxides; D012313:RNA; C025086:15-hydroperoxy-5,8,11,13-eicosatetraenoic acid; D007213:Indomethacin