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

FEBS Lett. 2005 Jul 18;579(18):3953-9. doi: 10.1016/j.febslet.2005.06.019.

Abstract

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.

MeSH terms

  • Blotting, Western
  • Cell Line
  • Down-Regulation*
  • Gene Expression Regulation*
  • Genes, Dominant
  • Humans
  • Interleukin-4 / metabolism
  • Interleukin-4 / physiology*
  • Interleukin-8 / biosynthesis*
  • Interleukin-8 / genetics
  • Interleukin-8 / metabolism
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Keratinocytes / metabolism*
  • Models, Genetic
  • Plasmids / metabolism
  • Promoter Regions, Genetic
  • RNA, Messenger / metabolism
  • Repressor Proteins / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • STAT6 Transcription Factor
  • Suppressor of Cytokine Signaling 1 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Trans-Activators / metabolism
  • Transcription, Genetic
  • Transfection
  • Tumor Necrosis Factor-alpha / metabolism*

Substances

  • Interleukin-8
  • Intracellular Signaling Peptides and Proteins
  • RNA, Messenger
  • Repressor Proteins
  • SOCS1 protein, human
  • STAT6 Transcription Factor
  • STAT6 protein, human
  • Suppressor of Cytokine Signaling 1 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Trans-Activators
  • Tumor Necrosis Factor-alpha
  • Interleukin-4