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

This study examined whether S100A8 and S100A9, which comprise a complexcalled calprotectin, are upregulated by exposure to sodium arsenite [As(III)]in nine lines of human-derived cells. HaCaT skin keratinocyte cells, U937 leukemicmonocyte cells, and UROtsa urothelial cells showed increased mRNA levels of S100A8and S100A9 after a 2-week exposure to As(III). To understand the mechanisms regulatingS100A9 upregulation in response to As(III), we tested S100A9 promoter-dependentluciferase activity in HaCaT cells transfected with S100A9 promoter (-1000/+429)-fusedluciferase cDNA. The results indicated that exposure to As(III) stimulated S100A9promoter-dependent luciferase activity. In addition, the transcription NF-E2-relatedfactor 2 (Nrf2) was strongly activated in HaCaT cells exposed to As(III). Sincetwo 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 luciferasecDNA. The results indicated that ARE2 is the responsible element for the activationof S100A9 transcription in response to As(III). This report is the first to demonstratethat As(III) enhanced S100A8 and S100A9 expression in human-derived cells andAs(III)-induced S100A9 expression is dependent on Nrf2 activation.