GLUCOCORTICOID REGULATION OF NATURAL CYTOTOXICITY - EFFECTS OF CORTISOL ON THE PHENOTYPE AND FUNCTION OF A CLONED HUMAN NATURAL-KILLER-CELLLINE

The ability of glucocorticoids to suppress cellular immune functions, including the cytotoxic activity of natural killer cells, is well know n. However, the molecular mechanism(s) of glucocorticoid-mediated supp ression of cellular cytotoxicity mediated by natural killer cells is n ot understood, We have investigated the effects of cortisol on protein expression and cytotoxic function of natural killer cells using NK3.3 , a well-characterized, cloned human natural killer cell line. Cortiso l, at concentrations up to 2 mu M, does not significantly alter the vi ability or proliferative capacity of NK3.3 cells. However, micromolar concentrations of cortisol induce the expression of a small set of pro teins which are not synthesized by NK3.3 cells in the absence of corti sol, and repress the synthesis of another set of proteins including se veral phenotypic determinants and cytokines. In the presence of added cortisol, the synthesis of perforin mRNA was partially repressed. Howe ver, the most striking effect of cortisol on this NK clone was its rep ression of granzyme A synthesis. In conjunction with the downregulatio n of adhesion proteins, NK3.3 cells cultured in the presence of cortis ol exhibit a reduced capacity to form conjugates with K562 target cell s. Whereas cortisol treatment of NK3.3 cells causes an approximately 5 0% decrease in their ability to form conjugates with K-562 target cell s, the cytotoxic function of these cells is completely abolished under the same conditions. This first report of hormonal regulation of gran zyme expression and the strong correlation between granzyme A repressi on and cytotoxic function suggests that cortisol may regulate NK funct ion by repression of granzyme A synthesis. In addition to demonstratin g the significant influence of cortisol on natural killer cell functio n, these studies provide a model system for elucidation of molecular m echanism(s) whereby glucocorticoids repress cellular immune function, especially with respect to natural killer cells. (C) 1997 Academic Pre ss.