Involvement of Nrf2 activation in the upregulation of S100A9 by exposure to inorganic arsenite.

This study examined whether S100A8 and S100A9, which comprise a complex called calprotectin, are upregulated by exposure to sodium arsenite [As(III)] in nine lines of human-derived cells. HaCaT skin keratinocyte cells, U937 leukemic monocyte cells, and UROtsa urothelial cells showed increased mRNA levels of S100A8 and S100A9 after a 2-week exposure to As(III). To understand the mechanisms regulating S100A9 upregulation in response to As(III), we tested S100A9 promoter-dependent luciferase activity in HaCaT cells transfected with S100A9 promoter (-1000/+429)-fused luciferase cDNA. The results indicated that exposure to As(III) stimulated S100A9 promoter-dependent luciferase activity. In addition, the transcription NF-E2-related factor 2 (Nrf2) was strongly activated in HaCaT cells exposed to As(III). Since two putative antioxidant response elements were found in the S100A9 promoter (ARE1, 5'-ACAGGCAGGG-3' from -897 to -887; ARE2, 5'-ATCTTCCGGAG-3' from -78 to -67), we constructed deletion mutants of each ARE on S100A9 promoter-fused luciferase cDNA. The results indicated that ARE2 is the responsible element for the activation of S100A9 transcription in response to As(III). This report is the first to demonstrate that As(III) enhanced S100A8 and S100A9 expression in human-derived cells and As(III)-induced S100A9 expression is dependent on Nrf2 activation.