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.
Masera
R
R
Dipartimento di Biomedicina, Università degli Studi di Torino, Ospedale San Luigi Gonzaga, Italy.
Gatti
G
G
Sartori
M L
ML
Carignola
R
R
Salvadori
A
A
Magro
E
E
Angeli
A
A
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology*; D000001:Calcimycin / Q000494:pharmacology*; D002118:Calcium / Q000097:blood / Q000502:physiology*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002147:Calmodulin / Q000037:antagonists & inhibitors / Q000097:blood; D002460:Cell Line; D003601:Cytotoxicity Tests, Immunologic; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000378:metabolism / Q000502:physiology*
D002121:Calcium Channel Blockers; D002147:Calmodulin; D000001:Calcimycin; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D002118:Calcium; D006854:Hydrocortisone