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

Abstract

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 x mL/7.75 x 10(6) 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 x mL/7.75 x 10(6) NK cells) and with interleukin-2 (IL-2; 100 IU/mL x 7.75 x 10(6) 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.

New Uses for Old Drugs and Their Application in Helminthology

“…DHEA has been demonstrated as a strong parasiticidal molecule in several systems. In another study, exogenous DHEA administration was shown to upregulate the immune system, specifically the cellular immune response, by increasing the number and function of natural killer cells [25]. However, our findings do not support this notion since IL-2 mRNA levels do not change in response to DHEA treatment [16].…”

Dehydroepiandrosterone, Dehydroepiandrosterone Sulfate and Related Steroids: Their Role in Inflammatory, Allergic and Immunological Disorders

“…An alternative mechanism of action of the steroids is suggested by Solerte et al who studied the effects of DHEAS on the natural killer activities of purified human NK cells. The increase in NK activity seen with DHEAS in vitro was dose-dependent and correlated with the amount of insulin like growth factor 1 (IGF-1) released to the supernatant under a variety of conditions [174], suggesting that the effects of DHEAS may have been mediated by IGF-1. Ueda et al have postulated another novel plasma membrane receptor for DHEAS, showing evidence supporting DHEAS activation of a sub-type of sigma receptor on macrophages, causing histamine release and a nociceptive stimulus [175].…”

Sex Steroid Metabolism in Human Peripheral Blood Mononuclear Cells Changes with Aging

“…DHEA administration to rodents increases IL-2 secretion (13) and natural killer (NK) cell cytotoxicity (14 -16) and decreases circulating IL-6 (17). Similarly, in vitro studies employing human immune cells show a DHEA-induced increase in IL-2 secretion (18) and NK cell cytotoxicity (19) and conversely an inhibition of IL-6 release (20). It is unclear to what extent these immune effects are due to direct effects of DHEA or mediated via downstream conversion to other steroids including the DHEA metabolites androstenediol and androstenetriol (Fig.…”