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Redox‐sensitive regulation of gene expression in human primary macrophages exposed to inorganic arsenic
Author(s) -
Bourdonnay Emilie,
Morzadec Claudie,
Fardel Olivier,
Vernhet Laurent
Publication year - 2009
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.22155
Subject(s) - gclm , hmox1 , gene expression , regulation of gene expression , biology , microbiology and biotechnology , transcription factor , arsenic trioxide , reactive oxygen species , gclc , oxidative stress , gene , chemistry , biochemistry , downregulation and upregulation , heme oxygenase , heme , apoptosis , enzyme
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.