Studies on the mechanism of human natural killer cell-mediated cytolysis. I. Modulation by dexamethasone and arachidonic acid.
Natural killer (NK) cell-mediated cytotoxicity, as measured by the lysis of the human erythroleukemic cell line K562, is inhibited by the glucocorticosteroid dexamethasone (DEX). Kinetic analysis revealed that DEX inhibits an early event(s) in the lytic mechanism and that the inhibition is both transient and readily reversible if DEX is removed. The inhibition is not due to the production of a DEX-induced inhibitory protein or decreased target-cell binding. Attempts to counter the effects of DEX through the addition of inducers of NK activity were unsuccessful. Neither the calcium ionophore A23187 nor exogenous cyclic GMP was able to reverse the inhibition by DEX. The addition of arachidonic acid (AA), a pharmacologically active metabolite of phospholipase A-2 activation, was also unsuccessful in reversing the effects of DEX. In fact, AA itself inhibited NK activity in a dose-dependent fashion. This inhibition was not due to reduced target binding and was observed even in the presence of indomethacin. It is concluded that DEX blocks an early membrane-signaling event necessary to activate the lytic mechanism and that inhibition was not through some alternative mechanism. Inhibition of NK activity by arachidonic acid is not yet understood but most likely is not a result of enhanced prostaglandin synthesis. Hence, the study of DEX and AA inhibition provides a new approach to unravel some of the intricacies surrounding NK-mediated tumor target destruction.
D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000494:pharmacology*; D001665:Binding Sites; D000001:Calcimycin / Q000494:pharmacology; D006152:Cyclic GMP / Q000096:biosynthesis; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D003609:Dactinomycin / Q000494:pharmacology; D003907:Dexamethasone / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000276:immunology*; D007700:Kinetics; D010741:Phospholipases A / Q000037:antagonists & inhibitors
D001095:Arachidonic Acids; D007166:Immunosuppressive Agents; D003609:Dactinomycin; D016718:Arachidonic Acid; D000001:Calcimycin; D003907:Dexamethasone; D010741:Phospholipases A; D006152:Cyclic GMP