Interplay in Vitro Between ACTH, β-Endorphin, and Glucocorticoids in the Modulation of Spontaneous and Lymphokine-Inducible Human Natural Killer (NK) Cell Activity

Abstract

Release of pro-opiomelanocortin (POMC)-derived peptides and glucocorticoids characterizes the activation of the hypothalamic–pituitary–adrenal (HPA) axis and represents a major adaptive response to stress. Both glucocorticoids and POMC-derived hormones are known to be crucial modifiers of the immune response. Natural killer (NK) cells are a lymphocyte subset deeply involved in immunosurveillance. Cortisol, the most important glucocorticoid hormone in humans, is a well-established inhibitor, whereas the two lymphokines, immune interferon (IFN-γ) and interleukin-2 (IL-2), are important physiological stimulators. In the present study, physiological as well as superphysiological concentrations of two POMC-derived peptides, ACTH and β-endorphin, were shown not only to affect in vitro spontaneous and lymphokine-inducible NK activity of peripheral blood mononuclear (PBM) cells, but also to modify cortisol-mediated inhibition. NK activity was measured in a 4-h cytotoxic assay using the cell line K562 as a target, after prior incubation with ACTH (10−8–l0−12M) and β-endorphin (10−8–l0−14M) in the presence or absence of cortisol(10−6MAl), IFN-γ (325 IU/ml), and IL-2 (25 IU/ml.). ACTH was ineffective in changing spontaneous NK activity at all concentrations, whereas β-endorphin enhanced NK cytotoxicity (p < .02). The concomitant exposure of PBM cells to the two POMC-derived peptides and IFN-γ or IL-2 significantly enhanced the lymphokine-induced boosting of NK activity. Moreover, ACTH and β-endorphin were able to significantly reduce the cortisol-dependent inhibition (p < .05). These data are compatible with the hypothesis that POMC-derived peptides have a role in the modulation of NK cell activity. It seems likely that in cases of activation of the HPA axis, ACTH and β-endorphin may effectively counteract the negative effects of glucocorticoids on NK cell activity, and prevent, at least in some instances, any overshooting of the glucocorticoid-dependent effect on immune cells.