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

摘要

Arsenic trioxide(As_2O_3)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.As_2O_3 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-kappa B(NF-kappa B);like As_2O_3,the selective NF-kappa B inhibitor(E)-3-[(4-methylphenyl)-sulfonyl]-2-propenenitrile(Bay 11-7082)strongly reduced survival of differentiating monocytes.The role of NF-kappa B in arsenic toxicity was also studied in promonocytic U937 cells during phorbol 12-myristate 13-acetate-induced macrophagic differentiation.In these cells,As_2O_3 first reduced DNA binding of p65 NF-kappa B and subsequently induced apoptosis.In addition,overexpression of the p65 NF-kappa B subunit,following stable infection with a p65 retroviral expressing vector,increased survival of As_2O_3-treated U937 cells.As_2O_3 specifically decreased protein levels of X-linked inhibitor of apoptosis protein and FLICE-inhibi-tory protein,two NF-kappa B-regulated genes in both U937 cells and blood monocytes during their differentiations.Finally,As_2O_3 was found to inhibit macrophagic differentiation of monocytic cells when used at cytotoxic concentrations;however,overexpression of the p65 NF-kappa B subunit in U937 cells reduced its effects toward differentiation.In contrast to monocytes,well differentiated mac-rophages were resistant to low concentrations of As_2O_3.Altogether,our study demonstrates that clinically relevant concentrations of As_2O_3 induced marked apoptosis of monocytic cells during in vitro macrophagic differentiation likely through inhibition of NF-kappa B-related survival pathways.