Inhibition of Human Natural Killer Cell Activity by (14R, 15S)-14,15-dihydroxy-5Z,8Z,10E,12E-icosatetraenoic Acid

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 81; no. 22; pp. 6914 - 6918
• Main Authors: Ramstedt, Urban, Serhan, Charles N., Lundberg, Ulf, Wigzell, Hans, Samuelsson, Bengt
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 01.11.1984; National Acad Sciences
• Subjects: Antibody dependent cell cytotoxicity; Antibody-Dependent Cell Cytotoxicity - drug effects; Biochemistry; Cell Adhesion - drug effects; Cytotoxicity; Cytotoxicity, Immunologic - drug effects; Dinoprostone; Esters; Humans; Hydroxyeicosatetraenoic Acids - pharmacology; Immunity, Innate - drug effects; Isomers; Killer Cells, Natural - drug effects; Leukocytes; Leukotriene B4 - analogs & derivatives; Leukotriene B4 - pharmacology; Leukotrienes; Lipoxygenase - physiology; Lymphocytes; Natural killer cells; Prostaglandins E - pharmacology; Structure-Activity Relationship; T lymphocytes; T-Lymphocytes, Cytotoxic - drug effects
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.81.22.6914

The interactions between products of the 15-lipoxygenase cascade and human natural killer (NK) cell activity have been studied. Addition of human leukocyte-derived (14R,15S)-14,15-dihydroxy-5Z,8Z,10E, 12E-icosatetraenoic acid (14,15-DiHETE) to the NK cytotoxicity assay against K562 target cells resulted in inhibition of NK cell activity, whereas addition of other 15-lipoxygenase-associated metabolites [i.e., (15S)-15-hydroperoxy-5Z,8Z,11Z, 13E-icosatetraenoic acid, (15S)-15-hydroxy-5Z,8Z,11Z, 13E-icosatetraenoic acid, and (8R,15S)- and (8S,15S)-8,15-dihydroxy-5Z,9E,11E, 13E-icosatetraenoic acid isomers] resulted in little or no inhibition of NK function. Dose-response studies indicate that leukocyte-derived 14,15-DiHETE and 14,15-DiHETE methyl ester, at micromolar concentrations, inhibit NK function even in the presence of 2.5% fetal calf serum. Synthetic 14,15-DiHETE prepared by total organic synthesis displayed similar biological activities over identical dose ranges. These icosanoids do not inhibit NK target cell binding and they exert only a variable effect in either antibody-dependent cytotoxicity or cytotoxic T-lymphocyte assays. These results demonstrate that the 14,15-DiHETE inhibits NK cell function in vitro. Moreover, they suggest that activation of the 15-lipoxygenase cascade and formation of 14,15-DiHETE in vivo may provide a mode of immune regulation.