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Dehydroepiandrosterone Sulfate Enhances Natural Killer Cell Cytotoxicity in Humans Via Locally Generated Immunoreactive Insulin-Like Growth Factor I¹

Department of Internal Medicine, Geriatrics and Gerontologic Clinic and School of Endocrinology and Metabolism, University of Pavia (S.B.S., M.F., L.C., E.F.), 27100 Pavia; the Laboratory of Endocrine and Metabolic Diseases, Ospedale Fornaroli (G.V.), Magenta; and the Department of Internal Medicine, Endocrine District, University of Brescia (A.G.), Brescia, Italy

Address all correspondence and requests for reprints to: Bruno Solerte, M.D., Department of Internal Medicine, University of Pavia, Ospedale S. Margherita, Piazza Borromeo 2, 27100 Pavia, Italy.

Experimental and clinical investigations suggest the hypothesis that dehydroepiandrosterone sulfate (DHEAS) can positively influence natural killer (NK) immunity via locally produced insulin-like growth factor I (IGF-I) from NK cells. In the present study, the NK cell cytotoxicity (NKCC) and IGF-I levels in the supernatant of NK cells were studied at baseline and after exposure to various molar concentrations of DHEAS (from 10^-5-10^-8 mol/L·mL/7.75 x 10⁶ NK cells) in healthy subjects of young and old age. DHEAS-induced NKCC was also determined after DHEAS coincubation with somatostatin-14 (10^-6 mol/L·mL/7.75 x 10⁶ NK cells) and with interleukin-2 (IL-2; 100 IU/mL·7.75 x 10⁶ NK cells). NK cells were previously isolated by Ficoll-Hypaque density gradient and then by immunomagnetic procedure; the purity obtained was 97 ± 1%. NKCC was determined against K562 tumoral targets. We observed that the increase in NKCC after DHEAS exposure was dose dependent and was correlated with the amount of IGF-I released in the supernatant of cultured NK cells. NKCC and IGF-I generation from NK cells were more elevated in healthy elder subjects than in healthy young subjects. The coincubation of DHEAS with somatostatin-14 significantly suppressed NKCC and IGF-I release from NK in both groups, whereas higher NKCC was found after DHEAS plus IL-2 exposure than after incubation with DHEAS alone. Taken together, this study suggests a role for NK-generated IGF-I in the modulation of NKCC by DHEAS in humans. Although DHEAS may contribute to the IL-2-mediated NKCC, its activity on NK cytolytic function can be dependent on a autocrine mechanism (IGF-I-mediated), probably independent of cytokine activation. The higher NKCC response to DHEAS found in old subjects than in younger might counterbalance the age-dependent decline in circulating DHEAS, thus contributing to maintain the pattern of NK immunity during aging.

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