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Myelo peroxidase hydrogen per oxide halide system as effector of neutrophil mediated tumor cell cyto toxicity



Myelo peroxidase hydrogen per oxide halide system as effector of neutrophil mediated tumor cell cyto toxicity



Journal of Immunology 126(4): 1295-1301



Human neutrophils activated by exposure to phorbol myristate acetate [PMA] were highly effective mediators of tumor cell cytotoxicity. Target cell injury was documented by a 51Cr release assay and by the loss of oncogenicity for test mice. The spectrum of susceptible tumor cells included the murine lines LSTRA [lymphoma], L1210 [lymphoma], EL-4 [lymphoma], YAC-1 [leukemia], and MPC-11 [plasmacytoma]. The potency of the human neutrophil as a killer cell was indicated by the low number of cells required (effector cell:target cell ratios as low as 1:2), the rapidity of target cell lysis (e.g., .ltoreq. 1 h), and the degree of 51Cr release (> 50% under most conditions). The involvement of neutrophil myeloperoxidase [MPD] was demonstrated by the inhibition of cytotoxicity by azide and cyanide, by the markedly impaired activity of neutrophils from a patient with hereditary MPD deficiency, and by the specific correction of this defect on addition of purified MPD. The participation of H2O2 was indicated by inhibition of cytotoxicity by catalase, but not by heated catalase or superoxide dismutase, by the absence of activity of neutrophils from patients with chronic granulomatous disease, and by the specific correction of this defect on addition of H2O2 or a peroxide-generating enzyme system (glucose oxidase). Target cell destruction required the presence of a halide cofactor.sbd.Cl-, I- or Br-. In the Cl- system, substantial enhancement of cytotoxicity was seen on addition of glucose. Partial inhibition of cytotoxicity was observed on addition of protein in the form of serum or albumin, an effect that was in part nullified by the addition of glucose and an increased number of neutrophil effector cells. Cytotoxicity was markedly inhibited by certain O radical scavengers, including ascorbic acid, 2-mercaptoethanol and methionine, but not oxidized methionine. Exposure of human neutrophils to PMA resulted in protein iodination as well as tumor cell cytotoxicity. Iodination and cytotoxicity displayed remarkably similar properties with respect to inhibitors, O radical scavengers, and phorbol ester dose-response characteristics. Structural specificity for various phorbol derivatives was also similar for iodination and cytotoxicity and matched that previously reported for tumor promotion and inflammatory properties of these compounds. The predominant iodination substrate was extracellular protein, indicating the secretion of MPD and H2O2. Evidently under these experimental conditions, the killing of tumor target cells by human neutrophils is mediated by the secretion of MPD and H2O2. These secretory products combine with extracellular halides to generate reactive oxidants that damage the target cells.

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Accession: 005951723

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