title: Second messenger function of arachidonic acid lipoxygenation products in human natural killer cell lysis?
abstract: Human natural killer (NK) cells were tested in the presence of several fatty acid oxygenase inhibitors such as nordihydroguaiaretic acid (NDGA), 5,8,11,14-eicosatetraynoic acid, 3-amino-1-m-(trifluoromethyl)-phenyl-2-pyrazoline (BW 755C), and indomethacin. All drugs inhibited NK lysis at the post-target cell-binding level at concentrations that also suppressed lipoxygenation of arachidonic acid, suggesting that such reactivity may be required for effector cell triggering. NDGA gave a 50% NK cell inhibition in the range of 10-30 microM and also suppressed antibody-dependent and lectin-dependent systems. Further evidence of the involvement of arachidonic acid lipoxygenation was found as NK activity could be reconstituted to NDGA-suppressed effector cells with several metabolites such as LTB4, LTB4 analogues, and hydroxyeicosatetraenoic acids lipoxygenated at C-5, C-12, and C-15. Cyclic nucleotides such as cGMP and cAMP could also reconstitute activity with optimal effects at approximately 10(-8) M. The combined evidence is compatible with a model for triggering lysis in which lipoxygenation products have a second messenger function. Whether arachidonic acid lipoxygenation is necessary for effector cells at all different activation/differentiation stages and whether the lipoxygenation products activate guanylic cyclase, protein kinase C, or some other target molecule remain to be further investigated.
mesh_terms: D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; D015117:5,8,11,14-Eicosatetraynoic Acid / Q000494:pharmacology; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism*; D002396:Catechols / Q000494:pharmacology; D000242:Cyclic AMP / Q000494:pharmacology; D006152:Cyclic GMP / Q000494:pharmacology; D003602:Cytotoxicity, Immunologic; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000276:immunology; D008084:Lipoxygenase / Q000378:metabolism*; D009637:Masoprocol; D011720:Pyrazoles / Q000494:pharmacology
chemical_list: D001095:Arachidonic Acids; D002396:Catechols; D011720:Pyrazoles; D015117:5,8,11,14-Eicosatetraynoic Acid; D016718:Arachidonic Acid; D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; D009637:Masoprocol; D000242:Cyclic AMP; D008084:Lipoxygenase; D006152:Cyclic GMP; D007213:Indomethacin