Interplay in vitro between ACTH, beta-endorphin, and glucocorticoids in the modulation of spontaneous and lymphokine-inducible human natural killer (NK) cell activity.
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-gamma) 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 beta-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)-10(-12) M) and beta-endorphin (10(-8)-10(-14) M) in the presence or absence of cortisol (10(-6) M), IFN-gamma (325 IU/ml), and IL-2 (25 IU/ml). ACTH was ineffective in changing spontaneous NK activity at all concentrations, whereas beta-endorphin enhanced NK cytotoxicity (p < .02). The concomitant exposure of PBM cells to the two POMC-derived peptides and IFN-gamma or IL-2 significantly enhanced the lymphokine-induced boosting of NK activity. Moreover, ACTH and beta-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 beta-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.
Gatti
G
G
Dipartimento di Scienze Cliniche e Biologiche, Università di Torino, Ospedale San Luigi Gonzaga, Italy.
Masera
R G
RG
Pallavicini
L
L
Sartori
M L
ML
Staurenghi
A
A
Orlandi
F
F
Angeli
A
A
D000324:Adrenocorticotropic Hormone / Q000031:analogs & derivatives / Q000494:pharmacology*; D000328:Adult; D003601:Cytotoxicity Tests, Immunologic; D004347:Drug Interactions; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000187:drug effects*; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D009000:Monocytes / Q000187:drug effects; D010446:Peptide Fragments / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D001615:beta-Endorphin / Q000494:pharmacology*
D007376:Interleukin-2; D010446:Peptide Fragments; D011994:Recombinant Proteins; D001615:beta-Endorphin; D007371:Interferon-gamma; D000324:Adrenocorticotropic Hormone; D006854:Hydrocortisone