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

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30 Citations (Scopus)

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
DOIs
Publication statusPublished - Aug 15 2014
Externally publishedYes

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Keywords

  • Human endothelial cells
  • IL-33
  • Nuclear repressor
  • Pulmonary hypertension
  • Soluble ST2

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Shao, D., Perros, F., Caramori, G., Meng, C., Dormuller, P., Chou, P. C., Church, C., Papi, A., Casolari, P., Welsh, D., Peacock, A., Humbert, M., Adcock, I. M., & Wort, S. J. (2014). 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. Biochemical and Biophysical Research Communications, 451(1), 8-14. https://doi.org/10.1016/j.bbrc.2014.06.111