Studies on the mechanism of cortisol inhibition of human natural killer cell activity: Effects of calcium entry blockers and calmodulin antagonists

Abstract

The role of Ca 2+ in mediating the inhibition by glucocorticoids of human natural killer (NK) activity was investigated using Ca 2+ entry blockers (verapamil and its desmethoxy-derivatives LU46973 and LU47093) and calmodulin antagonists (pimozide and two naphthalenesulfonamide derivatives, W-7 and W-13). Peripheral blood mononuclear (PBM) cell preparations were incubated for 20 h with 1×10 −6 M Cortisol and these agents in various combinations (concentration range: 1×10 −7 − 1×10 −5 M) and then assayed in a direct 4-h cytolytic assay using 51Cr-labeled K 562 target cells. Exposure to cortisol led to a significant reduction of NK cell activity (about 50% with respect to the spontaneous activity). Ca 2+ entry blockers displayed per se a dose-dependent depressive effect on cytotoxicity and gave significant enhancement of cortisol-dependent inhibition. Calmodulin antagonists were per se minimally effective but clearly amplified the cortisol-mediated inhibition. Raising extracellular Ca 2+ by CaCl 2 or intracellular Ca 2+ by the ionophore A23187 yelded an appreciable reduction of these effects. Our data are compatible with the view that extracellular and intracellular Ca 2+ play a role in the control of human NK cell activity. Moreover, it is conceivable that the mechanisms involved in glucocorticoid inhibition of NK cell activity involve Ca 2+-dependent pathways.