Mechanisms of tumour cell destruction by PMA-activated human neutrophils.
Phorbol myristate acetate (PMA)-activated neutrophils were found to destroy B lymphoblast tumour cells (Raji) as determined by the 51Cr release assay. The target cell lysis was prevented by azide, suggesting the involvement of the myeloperoxidase enzyme. Catalase and cytochrome c caused a marked impairment of the neutrophil-mediated cytolysis, whereas superoxide dismutase significantly enhanced the target cell destruction. These data indicate that hydrogen peroxide plays a key role in the target cell injury; superoxide anion appears to be devoid of direct cytotoxic activity, despite its requirement as a precursor of hydrogen peroxide. The target cell destruction required the presence of the iodide ion as oxidizable co-factor for the myeloperoxidase-hydrogen peroxide system. The chloride ion alone was uneffective. Inhibition of target cell metabolic pathways, involved in the cellular defences against oxidative injury, by the anti-neoplastic agent 1,3-bis-(2-chloroethyl)-1-nitrosurea (BCNU) resulted in an increased neutrophil-mediated cytolysis. Under the experimental conditions employed, PMA-activated neutrophils incubated with BCNU-treated Raji cells became cytotoxic also in the presence of the chloride ion alone as myeloperoxidase co-factor. Our results suggest that Raji target cell destruction by PMA-activated neutrophils depends on the myeloperoxidase-hydrogen peroxide-halide system. The cytolytic event is influenced by target cells themselves, which should be regarded as an active component of the cytotoxic system, capable of interfering with the lytic mediators of the effector cells.
D002051:Burkitt Lymphoma / Q000276:immunology*; D002330:Carmustine / Q000494:pharmacology; D002460:Cell Line; D002712:Chlorides; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D006801:Humans; D006861:Hydrogen Peroxide; D007454:Iodides; D009504:Neutrophils / Q000276:immunology*; D009195:Peroxidase / Q000378:metabolism; D010704:Phorbols / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*
D002712:Chlorides; D007454:Iodides; D010704:Phorbols; D006861:Hydrogen Peroxide; D009195:Peroxidase; D013755:Tetradecanoylphorbol Acetate; D002330:Carmustine