Epidemiologic studies demonstrated that long-term exposure to arsenic induces arsenical skin cancers, including Bowen's disease. Immunohistochemically, Bowen's disease shows proliferating and apoptotic characteristics. The transcription factors nuclear factor-kappa B (NF-kappa B) and activator protein-1 (AP-1) functionally regulate cell proliferation, transformation, and apoptosis. To investigate the mechanism of arsenic-induced apoptosis and related alterations in NF-kappa B and AP-1 activity, we exposed cultured human foreskin keratinocytes to different concentrations of sodium arsenite. At lower concentrations (< or =1 microM), arsenic induced keratinocyte proliferation and enhanced both NF-kappa B and AP-1 activity. At higher concentrations (> or =5 microM), arsenic induced keratinocyte apoptosis by the Fas/Fas ligand (FasL) pathway. At apoptosis induction concentrations, NF-kappa B activity was not enhanced; however, AP-1 activity was further enhanced. These results indicated that upregulation of NF-kappa B at lower arsenic concentrations was correlated with keratinocyte proliferation. In contrast, higher concentrations of arsenic enhanced AP-1 and induced Fas/FasL-associated apoptosis. The concentration-dependent arsenic effects on transcription factors activity can help to clarify the mechanisms in arsenic-induced proliferation and apoptosis in keratinocytes.