INDUCTION OF APOPTOSIS IN NK CELLS BY MONOCYTE-DERIVED REACTIVE OXYGEN METABOLITES

Human NK cells (with CD3(-)/56(+) phenotype) acquired features charact eristic of apoptosis after incubation with autologous monocytes, as re vealed by apoptotic nuclear morphology, degradation of DNA into oligon ucleosomal fragments, and reduced nuclear interchalation of propidium iodide. In contrast, T cells (CD3(+)/56(-)) remained non-apoptotic. Th e monocyte-induced apoptosis in NK cells was prevented by catalase, a scavenger of hydrogen peroxide; whereas superoxide dismutase (a scaven ger of superoxide anion), hydroxyl radical scavengers such as mannitol and deferoxamine, or the hypochlorus acid scavenger taurine did not p revent apoptosis. Sodium azide, a myeloperoxidase inhibitor, substanti ally reduced the monocyte-induced apoptosis in NK cells. Exogenous hyd rogen peroxide, at concentrations exceeding 1 mu M, induced apoptosis in both NK and T cells. Apoptosis induced by hydrogen peroxide occurre d independently of synthesis of protein or mRNA and was blocked by the endonuclease inhibitor aurin tricarboxylic acid. Furthermore, oxidati vely induced apoptosis in NK cells was inhibited by herbimycin A, indi cating that apoptosis was dependent on protein kinases. Two to five ti mes more hydrogen peroxide was required to induce apoptosis in T cells compared with NK cells. Similarly, NK cells were considerably more su sceptible to apoptosis induced by the topoisomerase II inhibitor etopo side or by gamma-irradiation than were T cells. We conclude that monoc yte-derived reactive oxygen metabolites kill NK cells by apoptosis and that NK cells are unusually sensitive to oxidatively as well as non-o xidatively induced apoptosis.