Abstract
Inorganic arsenic is an environmental contaminant toxic for key immune cells. We recently reported that low micromolar concentrations of arsenic trioxide (As~2~O~3~) alter functions and differentiation gene program of human macrophages. Particularly, prolonged treatment with As~2~O~3~ concomitantly reverses expression of a macrophage‐specific gene subset and triggers reactive oxygen species (ROS) production, suggesting a possible role of cell stress in As~2~O~3~ gene effects. This study was thus designed to determine whether redox‐sensitive signaling pathways could mediate gene expression in metalloid‐exposed macrophages. Our results show that As~2~O~3~‐dependent alterations of stress (HMOX1 and GCLM) and macrophage‐specific (MMP9, CCL22, and CXCL2) gene expression are not mediated by ROS or related signaling pathways. Notably, As~2~O~3~ alters neither activity of the redox‐sensitive transcription factor Sp1 nor that of AP‐1 or NF‐κB. In contrast, N‐acetylcysteine, a potent cysteine reductive compound, significantly prevents up‐regulation of HMOX1, GCLM, and CXCL2 genes, and repression of MMP9 and CCL22 genes induced by As~2~O~3~. In addition, we demonstrate that As~2~O~3~ markedly alters nuclear levels of Nrf2 and Bach1, two redox‐sensitive regulators of stress genes, and represses expression of the transcription factor EGR2 which is involved in mouse macrophage differentiation; such effects are reduced by N‐acetylcysteine. Finally, we report that genetic invalidation of EGR2 gene partially mimics metalloid effects; it significantly represses CCL22 gene expression and weakly induces that of CXCL2. In conclusion, our results demonstrate that As~2~O~3~ alters macrophage gene expression through redox‐sensitive signaling pathways unrelated to ROS production and reveal the transcription factor EGR2 as a new molecular target of arsenic. J. Cell. Biochem. 107: 537–547, 2009. © 2009 Wiley‐Liss, Inc.