Studies on the mechanism of cortisol inhibition of human natural killer cell activity: effects of calcium entry blockers and calmodulin antagonists.
The role of Ca2+ in mediating the inhibition by glucocorticoids of human natural killer (NK) activity was investigated using Ca2+ entry blockers (verapamil and its desmethoxy-derivatives LU46973 and LU47093) and calmodulin antagonists (pimozide and two naphthalenesulfopamide derivatives, W-7 and W-13). 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(-7) - 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% with respect to the spontaneous activity). Ca2+ 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 Ca2+ by CaCl2 or intracellular Ca2+ by the ionophore A23187 yelded an appreciable reduction of these effects. Our data are compatible with the view that extracellular and intracellular Ca2+ 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 Ca2+-dependent pathways.
Gatti
G
G
Dipartimento di Biomedicina, Università degli Studi di Torino, Ospedale San Luigi Gonzaga, Orbassano, Italy.
Masera
R
R
Cavallo
R
R
Sartori
M L
ML
Delponte
D
D
Carignola
R
R
Salvadori
A
A
Angeli
A
A
D000328:Adult; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002147:Calmodulin / Q000037:antagonists & inhibitors*; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology*; D066298:In Vitro Techniques; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008297:Male
D002121:Calcium Channel Blockers; D002147:Calmodulin; D002118:Calcium; D006854:Hydrocortisone