Interferon-gamma sensitizes human myeloid leukemia cells to death receptor-mediated apoptosis by a pleiotropic mechanism

The role of interferon (IFN)-gamma as a sensitizing agent in apoptosis indu ced by ligation of death receptors has been evaluated in human myeloid leuk emia cells. Incubation of U937 cells with IFN-gamma sensitized these cells to apoptosis induced by tumor necrosis factor-alpha, agonistic CD95 antibod y, and tumor necrosis factor-related apoptosis-inducing ligand, Other human myeloid leukemic cells were also sensitized by IFN-gamma to death receptor -mediated apoptosis. Treatment of U937 cells with IFN-gamma up-regulated th e expression of caspase-8 and potently synergized with death receptor ligat ion in the processing of caspase-8 and BID cleavage. Concomitantly, a marke d down-regulation of BCL-2 protein was also observed in cells incubated wit h IFN-gamma, Furthermore, the caspase-dependent generation of a 23-kDa frag ment of BCL-2 protein, the release of cytochrome c from mitochondria and th e activation of caspase-9 were also enhanced upon death receptor ligation i n IFN-gamma -treated cells. Ectopically expressed Bcl-2 protein inhibited I FN-gamma -induced sensitization to apoptosis. In summary, these results ind icate that IFN-gamma sensitizes human myeloid leukemic cells to a death rec eptor-induced, mitochondria-mediated pathway of apoptosis.