Suppression of natural killing in vitro by monocytes and polymorphonuclear leukocytes: requirement for reactive metabolites of oxygen.

Abstract

A B S T R A C T Natural killer cells spontaneously lyse certain tumor cells and may defend against malignancy. We have previously shown that natural killing (NK) by human peripheral blood mononuclear cells (PBMC) is suppressed in vitro by phorbol diester tumor promoters, including 12-0-tetradecanoylphorbol-13-acetate (TPA). We here demonstrate that suppression of NK is mediated by monocytes or polymorphonuclear leukocytes (PMN) and that suppression is dependent on the generation of reactive forms of molecular oxygen (RO), particularly hydrogen peroxide (H202). NK was suppressed not only by TPA but also by opsonized zymosan (yeast cell walls), which, like TPA, was not toxic to PBMC. Both TPA and zymosan stimulated the production of superoxide anion (O°) and H202 by PBMC. Production of RO correlated with suppression of NK. When PBMC were depleted of monocytes, the production of RO and the suppression of NK were both markedly reduced. Suppression could be restored by monocytes or PMN, both of which produced RO Suppression of NK by TPA was inhibited by catalase. Bovine superoxide dismutase had a limited effect on suppression, even in high concentration, and tyrosinecopper (II) complex, which also enhances dismutation of°2 to H202, had almost no effect on suppression.When H202 was directly generated enzymatically from glucose oxidase and glucose, NK was suppressed and suppression was reversed by catalase. NK was also suppressed by the enzymatic generation of°2 from xanthine oxidase and xanthine, but suppression under these conditions was again inhibited by catalase and not by superoxide dismutase, indicating that suppression was due to the secondary formation of H202 from O°. These results indicate that H202 is important in suppression of NK. Myeloperoxidase did not appear to play a role in suppression because inhibition of this enzyme by sodium azide, cyanide, or aminotriazole did not prevent suppression of NK. Suppression of NK was reversible; after exposure to zymosan, NK could be partially restored by the addition of catalase and superoxide dismutase or by the removal of zymosan. These studies demonstrate cellular regulation of NK by monocytes or polymorphonuclear leukocytes and indicate a role for RO in immunoregulation. INTRODUCTION Natural killer cells are mononuclear cells that spon-

Natural killer (NK) activity in peripheral blood lymphocytes of patients with benign and malignant breast disease

“…Experimental work in the mouse has suggested that oestrogens may influence NK levels (Seaman et al, 1978). Seaman et al (1979b) have shown that mouse oestradiol, which is itself non-toxic for NK cells (Seaman et al, 1978(Seaman et al, , 1979a, may suppress NK activity, perhaps via its effect on the bone marrow, though doses of oestradiol 9 times the physiological level are required for 4-6 weeks before a decline in activity is seen.…”

“…Seaman et al (1979b) have shown that mouse oestradiol, which is itself non-toxic for NK cells (Seaman et al, 1978(Seaman et al, , 1979a, may suppress NK activity, perhaps via its effect on the bone marrow, though doses of oestradiol 9 times the physiological level are required for 4-6 weeks before a decline in activity is seen. Neonatal administration of diethyl stilboestrol also suppresses NK activity (Kalland, 1980).…”

In vitro production and scavenging of hydrogen peroxide by D‐penicillamine. Relationship to copper availability

“…T helper cells appear to be particularly sensitive to inhibition by DP and copper sulfate (17,18), although a recent study suggests that B lymphocytes are more sensitive to H202 than are T celis (19). Natural killer cell function is also inhibited by reactive oxygen species released from activated monocytes and polyrnorphonuclear leukocytes (20). DP complexed with copper also has superoxide dismutase activity (21,22).…”

Two randomised phase II trials of subcutaneous interleukin-2 and histamine dihydrochloride in patients with metastatic renal cell carcinoma

“…A large number of in vitro and in vivo observations from independent laboratories have supported the observation of oxidative suppression of NK and T cells by phagocytes (i.e. monocytes, macrophages and neutrophils) (Seaman et al, 1982;Finke et al, 1993;Tartour et al, 1995;Hansson et al, 1996a;Kono et al, 1996;Saio et al, 2001). Hellstrand and co-workers have demonstrated that histamine protects NK and T cells against oxygen radical-induced dysfunction and apoptosis by specifically blocking the formation and release of hydrogen peroxide (H 2 O 2 ) from phagocytes, and moreover, maintains the activation of NK and T cells by IL-2 (Hellstrand and Hermodsson, 1986, 1991Hellstrand et al, , 1994aAsea et al, 1996;Hansson et al, 1996bHansson et al, , 1999.…”

“…However, the new paradigm of tumours arising and persisting in the setting of chronic inflammation (Pollard, 2004;Vakkila and Lotze, 2004) may represent one of several factors of importance for treatment failure. Among macrophage and neutrophil products, reactive oxygen species (ROS) may not only induce genomic instability (O'Byrne and Dalgleish, 2001) but also damage antitumour immune effector cells, especially natural killer (NK) and T cells (Seaman et al, 1982;Hellstrand et al, 1994a;Hansson et al, 1996a). Intratumoural macrophages isolated from melanoma metastases inhibit NK cell function by the release of ROS (Kono et al, 1996).…”