Interleukin (IL)-8 is a CXC chemokine induced by pro-inflammatory cytokines such as TNFalpha, IL-1beta and IL-6 in different cell types including keratinocytes. IL-4 regulation of TNFalpha-induced IL-8 expression is cell-type specific. In this study, we show that in the keratinocyte cell line HaCaT, IL-4 decreases TNFalpha-induced IL-8 mRNA expression. We then investigated the mechanism of IL-4 effect and showed that IL-4 downregulates TNFalpha-induced IL-8 promoter activity in luciferase reporter assays. Moreover, overexpression of either the endogenous JAK inhibitor SOCS-1 or a dominant negative form of the STAT6 transcription factor (STAT6DeltaC) interferes with the IL-4 inhibitory effect on IL-8 promoter. Finally we demonstrate, using a NF-kappaB-dependent promoter luciferase construct that IL-4 interferes, at least in part, with NF-kappaB transcriptional activity. Overall our results suggest that IL-4 regulates TNFalpha-induced IL-8 expression at a transcriptional level and this mechanism involves STAT6 and NF-kappaB transcription factors.