Format

Send to

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

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.

Author information

1
Section of Vascular Biology, National Heart and Lung Institute, Imperial College London, London, UK.
2
Faculté de Médecine, Université Paris-Sud, Paris, Clamart, France.
3
Dipartimento di Scienze Mediche, Sezione di Medicina Interna e Cardiorespiratoria, Centro Interdipartimentale per lo Studio delle Malattie Infiammatorie delle Vie Aeree e Patologie Fumo-Correlate, University of Ferrara, Ferrara, Italy.
4
Section of Vascular Biology, National Heart and Lung Institute, Imperial College London, London, UK; Department of Geriatrics, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
5
Airways Disease, National Heart and Lung Institute, UK.
6
Scottish Pulmonary Vascular Unit, University of Glasgow, UK.
7
Section of Vascular Biology, National Heart and Lung Institute, Imperial College London, London, UK. Electronic address: s.wort@imperial.ac.uk.

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.

KEYWORDS:

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

PMID:
25003325
DOI:
10.1016/j.bbrc.2014.06.111
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for Elsevier Science Icon for Spiral, Imperial College Digital Repository
Loading ...
Support Center