Interleukin-4 downregulates TNFalpha-induced IL-8 production in keratinocytes.
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.
Raingeaud
Joel
J
INSERM U461, Faculté de Pharmacie, 5 Rue JB Clément, 92296 Chatenay-Malabry, France. joel.raingeaud@cep.u-psud.fr
Pierre
Josiane
J
D015153:Blotting, Western; D002460:Cell Line; D015536:Down-Regulation; D005786:Gene Expression Regulation; D005799:Genes, Dominant; D006801:Humans; D015847:Interleukin-4 / Q000378:metabolism / Q000502:physiology*; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism*; D008957:Models, Genetic; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050800:STAT6 Transcription Factor; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D016209:Interleukin-8; D047908:Intracellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; C108944:SOCS1 protein, human; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4