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
File(s)
Accepted version
Author(s)
Type
Journal Article
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.
Date Issued
2014-07-05
Date Acceptance
2014-07-05
Citation
Biochemical and Biophysical Research Communications, 2014, 451 (1), pp.8-14
ISSN
1090-2104
Publisher
Elsevier
Start Page
8
End Page
14
Journal / Book Title
Biochemical and Biophysical Research Communications
Volume
451
Issue
1
Copyright Statement
© 2014 Elsevier. Licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/
Sponsor
Medical Research Council (MRC)
Medical Research Council (MRC)
Grant Number
G0801266
G1000758
Subjects
Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Biophysics
BIOCHEMISTRY & MOLECULAR BIOLOGY
BIOPHYSICS
IL-33
Soluble ST2
Pulmonary hypertension
Human endothelial cells
Nuclear repressor
NF-KAPPA-B
GENE-EXPRESSION
CYTOKINE IL-33
DUAL FUNCTION
ACTIVATION
PROLIFERATION
TRANSCRIPTION
INFLAMMATION
DISEASE
INTERLEUKIN-33
Base Sequence
Binding Sites
Case-Control Studies
Cells, Cultured
Endothelial Cells
Endothelium, Vascular
Familial Primary Pulmonary Hypertension
Gene Expression Regulation
Humans
Inflammation Mediators
Interleukin-33
Interleukin-6
Interleukins
Lung
Molecular Sequence Data
Promoter Regions, Genetic
Receptors, Cell Surface
Signal Transduction
0304 Medicinal And Biomolecular Chemistry
0601 Biochemistry And Cell Biology
1101 Medical Biochemistry And Metabolomics
Publication Status
Published