Raingeaud Joel, Pierre Josiane
INSERM U461, Faculté de Pharmacie, 5 Rue JB Clément, 92296 Chatenay-Malabry, France.
FEBS Lett. 2005 Jul 18;579(18):3953-9. doi: 10.1016/j.febslet.2005.06.019.
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.
白细胞介素（IL）-8是一种CXC趋化因子，由促炎细胞因子如肿瘤坏死因子α（TNFα）、白细胞介素-1β（IL-1β）和白细胞介素-6（IL-6）在包括角质形成细胞在内的不同细胞类型中诱导产生。IL-4对TNFα诱导的IL-8表达的调节具有细胞类型特异性。在本研究中，我们发现，在角质形成细胞系HaCaT中，IL-4可降低TNFα诱导的IL-8 mRNA表达。随后，我们研究了IL-4作用的机制，发现在荧光素酶报告基因检测中，IL-4可下调TNFα诱导的IL-8启动子活性。此外，内源性JAK抑制剂SOCS-1或STAT6转录因子的显性负性形式（STAT6DeltaC）的过表达会干扰IL-4对IL-8启动子的抑制作用。最后，我们使用一种依赖核因子κB（NF-κB）的启动子荧光素酶构建体证明，IL-4至少部分干扰NF-κB的转录活性。总体而言，我们的结果表明，IL-4在转录水平上调节TNFα诱导的IL-8表达，且该机制涉及STAT6和NF-κB转录因子。
