title: 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.
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.
authors.affiliation: Section of Vascular Biology, National Heart and Lung Institute, Imperial College London, London, UK.
authors.forename: Dongmin
authors.initials: D
authors.lastname: Shao
authors.affiliation: Faculté de Médecine, Université Paris-Sud, Paris, Clamart, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Perros
authors.affiliation: 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.
authors.forename: Gaetano
authors.initials: G
authors.lastname: Caramori
authors.affiliation: 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.
authors.forename: Chao
authors.initials: C
authors.lastname: Meng
authors.affiliation: Faculté de Médecine, Université Paris-Sud, Paris, Clamart, France.
authors.forename: Peter
authors.initials: P
authors.lastname: Dormuller
authors.affiliation: Airways Disease, National Heart and Lung Institute, UK.
authors.forename: Pai-Chien
authors.initials: PC
authors.lastname: Chou
authors.affiliation: Scottish Pulmonary Vascular Unit, University of Glasgow, UK.
authors.forename: Colin
authors.initials: C
authors.lastname: Church
authors.affiliation: 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.
authors.forename: Alberto
authors.initials: A
authors.lastname: Papi
authors.affiliation: 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.
authors.forename: Paolo
authors.initials: P
authors.lastname: Casolari
authors.affiliation: Scottish Pulmonary Vascular Unit, University of Glasgow, UK.
authors.forename: David
authors.initials: D
authors.lastname: Welsh
authors.affiliation: Scottish Pulmonary Vascular Unit, University of Glasgow, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Peacock
authors.affiliation: Faculté de Médecine, Université Paris-Sud, Paris, Clamart, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Humbert
authors.affiliation: Airways Disease, National Heart and Lung Institute, UK.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Adcock
authors.affiliation: Section of Vascular Biology, National Heart and Lung Institute, Imperial College London, London, UK. Electronic address: s.wort@imperial.ac.uk.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Wort
mesh_terms: D001483:Base Sequence; D001665:Binding Sites; D016022:Case-Control Studies; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D065627:Familial Primary Pulmonary Hypertension / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D007378:Interleukins / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D008168:Lung / Q000378:metabolism; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D011956:Receptors, Cell Surface / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C079241:IL1RL1 protein, human; C506536:IL33 protein, human; C508600:IL6 protein, human; D018836:Inflammation Mediators; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D015850:Interleukin-6; D007378:Interleukins; D011956:Receptors, Cell Surface
keywords: Human endothelial cells; IL-33; Nuclear repressor; Pulmonary hypertension; Soluble ST2