Streptomyces griseus strains isolated from indoor dust have been shown to synthesize valinomycin. In this report, we show that human peripheral blood lymphocytes treated with small doses (30 ng ml ؊1 ) of pure valinomycin or high-pressure liquid chromatography-pure valinomycin from S. griseus quickly show mitochondrial swelling and reduced NK cell activity. Larger doses (>100 ng/ml ؊1 ) induced NK cell apoptosis within 2 days. Within 2 h, the toxin at 100 ng ml ؊1 dramatically inhibited interleukin-15 (IL-15)-and IL-18-induced granulocyte-macrophage colony-stimulating factor and gamma interferon (IFN-␥) production by NK cells. However, IFN-␥ production induced by a combination of IL-15 and IL-18 was somewhat less sensitive to valinomycin, suggesting a protective effect of the cytokine combination against valinomycin. Thus, valinomycin in very small doses may profoundly alter the immune response by reducing NK cell cytotoxicity and cytokine production.Human peripheral blood lymphocytes (PBL) contain 5 to 20% NK cells, which can lyse certain tumor and normal cell lines without prior immunization. Upon activation, NK cells secrete cytokines such as gamma interferon (IFN-␥), tumor necrosis factor alpha, granulocyte-macrophage colony-stimulating factor (GM-CSF), and macrophage colony-stimulating factor (7,15,24). NK cells are thought to represent the first line defense in the immune system since they kill abnormal cells and simultaneously secrete cytokines to activate the other arms of the immune response.Interleukin-15 (IL-15) and IL-18 are cytokines which regulate NK cell function. IL-15 is required for NK cell maturation, and IL-18 is essential for NK cell activity (16,29). Valinomycin is an ionophore which is a cyclic-polypeptide-like dodecadepsipeptide whose folded conformation forms an inner cavity that can accommodate K ϩ but not other ions. For that reason, valinomycin is involved in a selective transport of K ϩ ions across the inner membrane of mitochondria (11,12). In rat ascites hepatoma cells, valinomycin induces apoptosis by disrupting the membrane potential of mitochondria and, when used at higher concentrations, causes apoptosis in many mammalian cell types (1, 10, 14, 21, 34). Andersson et al. (3) isolated Streptomyces griseus strains that produce valinomycin from an indoor environment. In schools and children's day care centers with dampness damage, such Streptomyces strains were frequently encountered (26).Here we report that pure commercial valinomycin and highpressure liquid chromatography (HPLC)-pure valinomycin from S. griseus inhibit human NK activity and cytokine production and induce apoptosis of NK cells at doses 10 to 500 times lower than those previously used. Thus, a toxin derived from bacteria that are abundant in the environment has the potential to cause immune suppression.
MATERIALS AND METHODSCell isolation and culture. Leukocyte-rich buffy coats were obtained from healthy blood donors (Finnish Red Cross Blood Transfusion Service, Helsinki, Finland). PBL were isolated by Ficoll-Paque...