Nuclear IL-33 is a transcriptional regulator of NF-κB p65 and induces endothelial cell activation

Biochem Biophys Res Commun. 2012 May 4;421(2):305-11. doi: 10.1016/j.bbrc.2012.04.005. Epub 2012 Apr 7.

Abstract

Interleukin (IL)-33, an IL-1 family member, acts as an extracellular cytokine by binding its cognate receptor, ST2. IL-33 is also a chromatin-binding transcriptional regulator highly expressed in the nuclei of endothelial cells. However, the function of IL-33 as a nuclear factor is poorly defined. Here, we show that IL-33 is a novel transcriptional regulator of the p65 subunit of the NF-κB complex and is involved in endothelial cell activation. Quantitative reverse transcriptase PCR and Western blot analyses indicated that IL-33 mediates the expression of intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 in endothelial cells basally and in response to tumor necrosis factor-a-treatment. IL-33-induced ICAM-1/VCAM-1 expression was dependent on the regulatory effect of IL-33 on the nuclear factor (NF)-κB pathway; NF-κB p65 expression was enhanced by IL-33 overexpression and, conversely, reduced by IL-33 knockdown. Moreover, NF-κB p65 promoter activity and chromatin immunoprecipitation analysis revealed that IL-33 binds to the p65 promoter region in the nucleus. Our data provide the first evidence that IL-33 in the nucleus of endothelial cells participates in inflammatory reactions as a transcriptional regulator of NF-κB p65.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Adhesion / genetics
  • Cell Nucleus / metabolism*
  • Cells, Cultured
  • Endothelial Cells / metabolism*
  • Gene Knockdown Techniques
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Inflammation / genetics
  • Intercellular Adhesion Molecule-1 / genetics
  • Interleukin-33
  • Interleukins / metabolism*
  • Monocytes / physiology
  • Promoter Regions, Genetic
  • Transcription Factor RelA / genetics*
  • Transcriptional Activation*
  • Tumor Necrosis Factor-alpha / pharmacology
  • Vascular Cell Adhesion Molecule-1 / genetics

Substances

  • IL33 protein, human
  • Interleukin-33
  • Interleukins
  • Transcription Factor RelA
  • Tumor Necrosis Factor-alpha
  • Vascular Cell Adhesion Molecule-1
  • Intercellular Adhesion Molecule-1