A Potential Role for Hypochlorous Acid in Granulocyte-Mediated Tumor Cell Cytotoxicity

Abstract

The myeloperoxidase-H2O2-Cl– system of the human granulocyte forms e powerful cytotoxic system, but the final mediator of target cell destruction is unclear. In this study, we have investigated the cytotoxic potential of hypochlorous acid, a known product of the myeloperoxidase-H2O2-CI system. Human granulocytes stimulated with phorbol myristate acetate were able to mediate cytotoxicity against a T-lymphoblast target cell (CEM). Cytolysis was inhibited by catalase and myeloperoxidase inhibitors but stimulated by superoxide dismutase. These results indicated a role for both H2O2 and myeloperoxidase in the cytolytic event. In order to characterize the cytotoxicity of hypochlorous acid, a cell-free system was designed. As little as 7.5 nmoles of hypochlorous acid mediated a cytotoxic effect comparable to that of the granulocyte system. Compounds known to scavenge hypochlorous acid prevented CEM lysis in both the cell-free hypochlorous acid system and the granulocyte system. Neither hydroxyl radical nor singlet oxygen scavengers had any inhibitory effect in either of these systems. Thus, intact human granulocytes mediated cytotoxicity against CEMs via a myeloperoxidase-H2O2-dependent mechanism, and the lytic species has characteristics similar to hypochlorous acid. These results suggest that hypochlorous acid may be a common mediator of myeloperoxidase-dependent cytotoxic events.