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Originally published In Press as doi:10.1074/jbc.M100815200 on February 14, 2001

J. Biol. Chem., Vol. 276, Issue 21, 17779-17787, May 25, 2001
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Interferon-gamma Sensitizes Human Myeloid Leukemia Cells to Death Receptor-mediated Apoptosis by a Pleiotropic Mechanism*

Nieves VarelaDagger §, Cristina Muñoz-Pinedo||, Carmen Ruiz-Ruiz||, Gema Robledo, Miriam PedrosoDagger , and Abelardo López-Rivas**

From the  Instituto de Parasitología y Biomedicina, Consejo Superior de Investigaciones Científicas, calle Ventanilla 11, 18001 Granada, Spain and the Dagger  Centro Nacional de Sanidad Agropecuaria, carretera de Tapaste y Autopista Nacional, San José de las Lajas, La Habana, Cuba

The role of interferon (IFN)-gamma as a sensitizing agent in apoptosis induced by ligation of death receptors has been evaluated in human myeloid leukemia cells. Incubation of U937 cells with IFN-gamma sensitized these cells to apoptosis induced by tumor necrosis factor-alpha , agonistic CD95 antibody, 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 the expression of caspase-8 and potently synergized with death receptor ligation in the processing of caspase-8 and BID cleavage. Concomitantly, a marked down-regulation of BCL-2 protein was also observed in cells incubated with IFN-gamma . Furthermore, the caspase-dependent generation of a 23-kDa fragment of BCL-2 protein, the release of cytochrome c from mitochondria and the activation of caspase-9 were also enhanced upon death receptor ligation in IFN-gamma -treated cells. Ectopically expressed Bcl-2 protein inhibited IFN-gamma -induced sensitization to apoptosis. In summary, these results indicate that IFN-gamma sensitizes human myeloid leukemic cells to a death receptor-induced, mitochondria-mediated pathway of apoptosis.

* This work was supported in part by Ministerio de Educación y Cultura Grants 1FD97-0514-C02-01 and SAF2000-0118-C03-01 and by Consejo Superior de Investigaciones Científicas/Ministerio de Ciencia, Technología y Medio Ambiente Grant 99CU0004 (to A.L.-R.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Recipient of a fellowship from Junta de Andalucia.

|| Both authors contributed equally to this work.

** To whom correspondence should be addressed. Tel.: 34-958-80-51-88; Fax: 34-958-20-33-23; E-mail: alrivas@ipb.csic.es.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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