N. Varela et al., Interferon-gamma sensitizes human myeloid leukemia cells to death receptor-mediated apoptosis by a pleiotropic mechanism, J BIOL CHEM, 276(21), 2001, pp. 17779-17787
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.