Nuclear IL-33 regulates soluble ST2 receptor and IL-6 expression in primary human arterial endothelial cells and is decreased in idiopathic pulmonary arterial hypertension

Biochem Biophys Res Commun. 2014 Aug 15;451(1):8-14. doi: 10.1016/j.bbrc.2014.06.111. Epub 2014 Jul 5.


Idiopathic pulmonary arterial hypertension (IPAH) is an incurable condition leading to right ventricular failure and death and inflammation is postulated to be associated with vascular remodelling. Interleukin (IL)-33, a member of the "alarmin" family can either act on the membrane ST2 receptor or as a nuclear repressor, to regulate inflammation. We show, using immunohistochemistry, that IL-33 expression is nuclear in the vessels of healthy subjects whereas nuclear IL-33 is markedly diminished in the vessels of IPAH patients. This correlates with reduced IL-33 mRNA expression in their lung. In contrast, serum levels of IL-33 are unchanged in IPAH. However, the expression of the soluble form of ST2, sST2, is enhanced in the serum of IPAH patients. Knock-down of IL-33 in human endothelial cells (ECs) using siRNA is associated with selective modulation of inflammatory genes involved in vascular remodelling including IL-6. Additionally, IL-33 knock-down significantly increased sST2 release from ECs. Chromatin immunoprecipitation demonstrated that IL-33 bound multiple putative homeodomain protein binding motifs in the proximal and distal promoters of ST2 genes. IL-33 formed a complex with the histone methyltransferase SUV39H1, a transcriptional repressor. In conclusion, IL-33 regulates the expression of IL-6 and sST2, an endogenous IL-33 inhibitor, in primary human ECs and may play an important role in the pathogenesis of PAH through recruitment of transcriptional repressor proteins.

Keywords: Human endothelial cells; IL-33; Nuclear repressor; Pulmonary hypertension; Soluble ST2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Binding Sites
  • Case-Control Studies
  • Cells, Cultured
  • Endothelial Cells / metabolism
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / metabolism
  • Familial Primary Pulmonary Hypertension / metabolism*
  • Familial Primary Pulmonary Hypertension / pathology
  • Gene Expression Regulation
  • Humans
  • Inflammation Mediators / metabolism
  • Interleukin-1 Receptor-Like 1 Protein
  • Interleukin-33
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism*
  • Interleukins / blood
  • Interleukins / genetics
  • Interleukins / metabolism*
  • Lung / metabolism
  • Molecular Sequence Data
  • Promoter Regions, Genetic
  • Receptors, Cell Surface / blood
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism*
  • Signal Transduction


  • IL1RL1 protein, human
  • IL33 protein, human
  • IL6 protein, human
  • Inflammation Mediators
  • Interleukin-1 Receptor-Like 1 Protein
  • Interleukin-33
  • Interleukin-6
  • Interleukins
  • Receptors, Cell Surface