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

Dongmin Shao, Frédéric Perros, Gaetano Caramori, Chao Meng, Peter Dormuller, Pai-Chien Chou, Colin Church, Alberto Papi, Paolo Casolari, David Welsh, Andrew Peacock, Marc Humbert, Ian M. Adcock, Stephen J. Wort*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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.
Original languageEnglish
Pages (from-to)8-14
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume451
Issue number1
Early online date5 Jul 2014
DOIs
Publication statusPublished - 15 Aug 2014

Keywords

  • IL-33
  • soluble ST2
  • pulmonary hypertension
  • human endothelial cells
  • nuclear repressor

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