Involvement of Ca2+-dependent pathways in the inhibition of human natural killer (NK) cell activity by cortisol.

The role of Ca2+ as a second messenger of the glucocorticoid inhibition of human natural killer (NK) cell activity was evaluated using Ca2+ entry blockers (verapamil and its desmethoxy derivatives LU46973 and LU47093), calmodulin antagonists (pimozide and two naphthalensulfonamide derivatives, W-7 and W-13), the Ca2+ channel agonist BAY K 8644 and the calcium ionophore A23187. Peripheral blood mononuclear (PBM) cell preparations were incubated for 20 h with 1 x 10(-6) M cortisol and these agents in various combinations (concentration range: 1 x 10(-9) -1 x 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% vs. spontaneous activity). Ca2+ entry blockers and calmodulin antagonists were per se minimally effective, but significantly enhanced cortisol-dependent inhibition of NK cell activity. Raising extracellular Ca2+ by CaCl2 or intracellular Ca2+ by the calcium channel agonist BAY K 8644 or the ionophore A23187 resulted in an appreciable reduction of these effects. Similar results were obtained when these substances were added to monocyte-depleted or NK cell-enriched suspensions exposed to cortisol. Our data are consistent with the view that extra- and intracellular Ca2+ plays a role in the control of human NK cell activity. It is also conceivable that both calcium flux into the cell and the calcium calmodulin system are involved in the cortisol-induced inhibition of natural cytotoxicity.