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TOXICOLOGY

Arsenic Trioxide Induces Apoptosis of Human Monocytes during Macrophagic Differentiation through Nuclear Factor-B-Related Survival Pathway Down-Regulation

Institut National de la Sante et de la Recherche Medicale U620, Détoxication et Réparation Tissulaire, Université de Rennes 1, Rennes, France (A.L., C.M., O.F., L.V.); Institut National de la Sante et de la Recherche Medicale U517, Mort Cellulaire et Cancer, Facultés de Médecine et Pharmacie, Dijon, France (D.M., O.M.); and Laboratoire d'Hématologie-Immunologie, Centre Hospitalier Universitaire Pontchaillou, Rennes, France (O.F.)

Arsenic trioxide (As₂O₃) is known to be toxic toward leukemia cells. In this study, we determined its effects on survival of human monocytic cells during macrophagic differentiation, an important biological process involved in the immune response. As₂O₃ used at clinically relevant pharmacological concentrations induced marked apoptosis of human blood monocytes during differentiation with either granulocyte-macrophage colony-stimulating factor or macrophage colony-stimulating factor. Apoptosis of monocytes was associated with increased caspase activities and decreased DNA binding of p65 nuclear factor-B (NF-B); like As₂O₃, the selective NF-B inhibitor (E)-3-[(4-methylphenyl)-sulfonyl]-2-propenenitrile (Bay 11-7082) strongly reduced survival of differentiating monocytes. The role of NF-B in arsenic toxicity was also studied in promonocytic U937 cells during phorbol 12-myristate 13-acetate-induced macrophagic differentiation. In these cells, As₂O₃ first reduced DNA binding of p65 NF-B and subsequently induced apoptosis. In addition, overexpression of the p65 NF-B subunit, following stable infection with a p65 retroviral expressing vector, increased survival of As₂O₃-treated U937 cells. As₂O₃ specifically decreased protein levels of X-linked inhibitor of apoptosis protein and FLICE-inhibitory protein, two NF-B-regulated genes in both U937 cells and blood monocytes during their differentiations. Finally, As₂O₃ was found to inhibit macrophagic differentiation of monocytic cells when used at cytotoxic concentrations; however, overexpression of the p65 NF-B subunit in U937 cells reduced its effects toward differentiation. In contrast to monocytes, well differentiated macrophages were resistant to low concentrations of As₂O₃. Altogether, our study demonstrates that clinically relevant concentrations of As₂O₃ induced marked apoptosis of monocytic cells during in vitro macrophagic differentiation likely through inhibition of NF-B-related survival pathways.

Address correspondence to: Laurent Vernhet, Unité INSERM U620, Dé-toxication et Réparation Tissulaire, Faculté des Sciences Pharmaceutiques et Biologiques, Université de Rennes 1, 2 avenue du Pr. Léon Bernard, 35043 Rennes, France. E-mail: laurent.vernhet{at}rennes.inserm.fr

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