Abstract
Arsenite has been reported to exert dose‐dependent dual effects: triggering apoptosis at relatively high concentrations, whereas inducing partial differentiation at low concentrations in leukemia cells. However, the relevant molecular mechanisms of its action at low and nonapoptotic concentrations remain to be elucidated. We examined the effect of arsenite on activation of key transcription factors in cultured U937 human monocytes/macrophages. Electrophoretic mobility shift assay (EMSA), protein/DNA array and luciferase reporter assay were used to analyze the effect of arsenite on the functional activities of transcription factors. Protein/DNA array analysis showed that activation of E2F was seen after 6‐h exposure to 1 and 10 μM arsenite. In contrast, activation of NF‐κB took place only at 1 μM arsenite, whereas 10 μM arsenite showed no recognizable effect on this nuclear transcription factor in the protein/DNA array analysis. EMSA using a NF‐κB consensus probe indicates the functional activation of RelB/p50 in the presence of 1 μM arsenite, confirming the above results. Luciferase reporter assay for NF‐κB showed activation of NF‐κB in the presence of 1 μM arsenite. Interleukin (IL)‐8 and B‐cell‐activating factor of the tumor necrosis factor family (BAFF) mRNA expression, which have been shown to be regulated through NF‐κB, were activated in the presence of 1 μM arsenite. These results support the hypothesis that the primary action of nonapoptotic concentrations of arsenite in this cell line is activation of NF‐κB, signaling as a decision maker for end results such as inflammation disease or cancer. This finding offers the possibility of providing a logical explanation for the observations made by many scientists that chronic exposure of human populations to low doses of arsenic is significantly correlated to clinical signs of inflammation in many tissues. © 2008 Wiley Periodicals, Inc. J Biochem Mol Toxicol 22:136–146, 2008; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20222