Redox-sensitive regulation of gene expression in human primary macrophages exposed to inorganic arsenic.
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-kappaB. 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.
Inserm U620, Group Toxicité des contaminants de l'environnement, 2 avenue du Pr. Léon Bernard, 35043 Rennes, France.
Emilie
E
Bourdonnay
Claudie
C
Morzadec
Olivier
O
Fardel
Laurent
L
Vernhet
D000077237:Arsenic Trioxide; D001152:Arsenicals; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism; D054426:Chemokine CXCL2 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000187:drug effects*; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D010087:Oxides / Q000633:toxicity*; D017382:Reactive Oxygen Species / Q000378:metabolism
D001152:Arsenicals; D050976:Basic-Leucine Zipper Transcription Factors; D054426:Chemokine CXCL2; D051267:NF-E2-Related Factor 2; D010087:Oxides; D017382:Reactive Oxygen Species; D000077237:Arsenic Trioxide