The effects of cortisol and prostaglandin E2 on preparations of human peripheral blood mononuclear cells that mediate natural killer cytotoxicity were evaluated. Natural killer cell activity was measured using 51Cr-labelled K562 target cells and effector to target cell (E:T) ratios of 50:1, 25:1, 12.5:1 and 6:1. In vitro preincubation of mononuclear cell preparations for 20 h with 1 X 10(-8) to 1 X 10(-5) M cortisol resulted in a significant decrease of natural killer cell activity. The magnitude of the suppression was directly related to the steroid concentration and inversely related to the E:T ratio. Exposure of cortisol-treated mononuclear cells to 1 X 10(-6) M prostaglandin E2 resulted in a significantly higher level of inhibition than after treatment with the two agents singularly. In contrast, the concomitant incubation with 1 X 10(-5) to 1 X 10(-4) M theophylline, or with 1 X 10(-6) to 1 X 10(-5) M isobutyl-methylxanthine, two widely used phosphodiesterase inhibitors, failed to demonstrate a significant enhancement of cortisol-induced suppression. Prostaglandin E2-dependent inhibition, on the other hand, was more intense after the inhibition of phosphodiesterase activity. Taken together, these results show that cortisol at physiological concentrations has the property of depressing human natural killer cell activity in vitro and suggest that endogenous glucocorticoids play a role in the in vivo regulation of this natural cytotoxicity. Additionally, cortisol and prostaglandin E2 are additive inhibitors of natural killer cell activity. Since the effect of cortisol in our experiments was not changed by theophylline or isobutyl-methylxanthine it is conceivable that the hormone acts at a level different from the adenylate cyclase/phosphodiesterase system.
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