Aquaporin-3 (AQP3) is a water/glycerol-transporting protein that is strongly expressed at the plasma membranes of keratinocytes in skin. There is evidence for involvement of AQP3-facilitated water and glycerol transport in skin hydration and wound repair, respectively. In this study, we show that tumor necrosis factor-alpha (TNF-alpha) and TNF receptor-1 signaling decreased AQP3 protein expression and plasma membrane water permeability in DJM-1 keratinocytes. TNF-alpha also decreased AQP3 mRNA expression and promoter activity, indicating that TNF-alpha suppresses AQP3 gene transcription. In addition, inhibitors of p38 and extracellular signal-regulated kinase (ERK) abolished the effect of TNF-alpha on AQP3 expression level, whereas inhibitors for NF-kappa B did not. These data indicate that TNF-alpha decreases AQP3 gene expression through p38 and ERK activation, and suggest that the decrease in AQP3 expression caused by TNF-alpha might be related to the phenotypes of skin inflammation, such as dry skin. (C) 2009 Elsevier Inc. All rights reserved.