Interleukin-4 downregulates TNFα-induced IL-8 production in keratinocytes

Interleukin (IL)-8 is a CXC chemokine induced by pro-inflammatory cytokines such as TNFα, IL-1β and IL-6 in different cell types including keratinocytes. IL-4 regulation of TNFα-induced IL-8 expression is cell-type specific. In this study, we show that in the keratinocyte cell line HaCaT, IL-4 decreases TNFα-induced IL-8 mRNA expression. We then investigated the mechanism of IL-4 effect and showed that IL-4 downregulates TNFα-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 (STAT6ΔC) interferes with the IL-4 inhibitory effect on IL-8 promoter. Finally we demonstrate, using a NF-κB-dependent promoter luciferase construct that IL-4 interferes, at least in part, with NF-κB transcriptional activity. Overall our results suggest that IL-4 regulates TNFα-induced IL-8 expression at a transcriptional level and this mechanism involves STAT6 and NF-κB transcription factors.