Effects of CRH, acth and the corticostatin HP-4 on the spontaneous NK cell activity and susceptibility to endogenous modifiers

Abstract

Natural killer (NK) cells are mononuclear leukocytes which are thought to play an important role in immunosurveillance; in the elderly a progressive reduction occurs both of their spontaneous activity and of their responsiveness to positive modulators such as immune interferon (IFN-y) and interleukin-2 (IL-2). NK cells represent also a reliable model to study immunomodulatory properties of the hypothalamic-pituitary-adrenal (HPA) system, since cortisol (F) is a well defined inhibitor of their activity whereas proopiomelanocortin (POMC)-derived peptides may counteract this effect. Corticostatins (CS)-defensins are a family of peptides recently purified from cells capable of phagocytic activity; they are able to inhibit the steroidogenic activity of ACTH and to enhance internalization and/or killing of intracellular pathogens. We have investigated the effects in vitro of corticotropin releasing hormone (CRH), ACTH and CS HP-4 on human NK cell activity. Peripheral blood mononuclear (PBM) cells from healthy donors were incubated with CRH (10(-14)-10(-11) M). ACTH (10(-12)-10(-8) M) and HP-4 (10(-10)-10(-8) M) in the presence or absence of F (10(-6) M) or IFN-y (325 IU//ml) or IL-2 (25 IU/ml). NK cell activity was measured in a 4-h cytotoxic assay using K562 cells as a target. CRH was able to significantly reduce the spontaneous and IL-2-induced NK activity and to significantly potentiate the F-dependent inhibition. ACTH was per se ineffective on the spontaneous NK activity, but was able to augment the enhancing effects of IFN-y and IL-2, and to reduce the degree of inhibition obtainable with the glucocorticoid. HP-4 was able to enhance the F-dependent inhibition of PBM preparations. Our results are consistent with an immunomodulatory role for CRH, ACTH and CS, specially in conditions of high concentrations of glucocorticoids. Since in elderly has been demonstrated a condition of hypercortisolism, we suggest that complex steroid-peptides interactions are involved in the net effect of HPA axis on immune functions in senescence, and that such interactions involve paracrine/autocrine CS.