Toll-like receptor 4 mediates endothelial cell activation through NF-κB but is not associated with endothelial dysfunction in patients with rheumatoid arthritis.

<h4>Objective</h4>To investigate the effects of TLR4 antagonism on human endothelial cells activation and cytokine expression, and whether the Asp299Gly TLR4 polymorphism is associated with better endothelial function in patients with rheumatoid arthritis (RA).<h4>Methods</h4>...

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Autores principales:	Rossella Menghini, Umberto Campia, Manfredi Tesauro, Arianna Marino, Valentina Rovella, Giuseppe Rodia, Francesca Schinzari, Barbara Tolusso, Nicola di Daniele, Massimo Federici, Angelo Zoli, Gianfranco Ferraccioli, Carmine Cardillo
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/7b64eb30c17443a592e3cd20aca7cb05
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spelling	oai:doaj.org-article:7b64eb30c17443a592e3cd20aca7cb052021-11-18T08:16:09ZToll-like receptor 4 mediates endothelial cell activation through NF-κB but is not associated with endothelial dysfunction in patients with rheumatoid arthritis.1932-620310.1371/journal.pone.0099053https://doaj.org/article/7b64eb30c17443a592e3cd20aca7cb052014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24918924/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Objective</h4>To investigate the effects of TLR4 antagonism on human endothelial cells activation and cytokine expression, and whether the Asp299Gly TLR4 polymorphism is associated with better endothelial function in patients with rheumatoid arthritis (RA).<h4>Methods</h4>Human aortic endothelial cells (HAECs) were treated with lipopolysaccharide (LPS), OxPAPC, and free fatty acids (FFA) at baseline and after incubation with the TLR4 antagonist eritoran (E5564). Cytokine expression was assessed by quantitative real-time PCR. In vivo endothelial function was assessed as brachial artery flow-mediated dilation (FMD) in RA patients with the wild type gene (aa) and with the Asp299Gly TLR4 polymorphic variant (ag).<h4>Results</h4>In HAEC, TLR4 antagonism with eritoran inhibited LPS-induced mRNA expression of IL-6, IL-8, TNFα, CCL-2, VCAM and ICAM (P<0.05 for all) and inhibited Ox-PAPC-induced mRNA expression of IL-8 (P<0.05) and IL-6, albeit not to a statistically significant level (p = 0.07). In contrast, eritoran did not affect FFA-induced mRNA expression of IL-6 (P>0.05). In 30 patients with RA (15 with the ag allele) undergoing measurement of FMD, no differences in FMD and plasma levels of IL-6, IL-8, VCAM, and ICAM were found between the aa and the ag phenotype (P>0.05 for all).<h4>Conclusions</h4>TLR4 signaling in endothelial cells may be triggered by LPS and oxidized phospholipids, leading to endothelial activation and inflammation, which are inhibited by eritoran. Our in vivo investigation, however, does not support an association between the Asp299Gly TLR4 polymorphism and improved endothelium-dependent vasodilator function in patients with RA. Further study is needed to better understand the potential role of TLR4 on endothelial dysfunction in this and other patient populations.Rossella MenghiniUmberto CampiaManfredi TesauroArianna MarinoValentina RovellaGiuseppe RodiaFrancesca SchinzariBarbara TolussoNicola di DanieleMassimo FedericiAngelo ZoliGianfranco FerraccioliCarmine CardilloPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 6, p e99053 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Rossella Menghini Umberto Campia Manfredi Tesauro Arianna Marino Valentina Rovella Giuseppe Rodia Francesca Schinzari Barbara Tolusso Nicola di Daniele Massimo Federici Angelo Zoli Gianfranco Ferraccioli Carmine Cardillo Toll-like receptor 4 mediates endothelial cell activation through NF-κB but is not associated with endothelial dysfunction in patients with rheumatoid arthritis.
description	<h4>Objective</h4>To investigate the effects of TLR4 antagonism on human endothelial cells activation and cytokine expression, and whether the Asp299Gly TLR4 polymorphism is associated with better endothelial function in patients with rheumatoid arthritis (RA).<h4>Methods</h4>Human aortic endothelial cells (HAECs) were treated with lipopolysaccharide (LPS), OxPAPC, and free fatty acids (FFA) at baseline and after incubation with the TLR4 antagonist eritoran (E5564). Cytokine expression was assessed by quantitative real-time PCR. In vivo endothelial function was assessed as brachial artery flow-mediated dilation (FMD) in RA patients with the wild type gene (aa) and with the Asp299Gly TLR4 polymorphic variant (ag).<h4>Results</h4>In HAEC, TLR4 antagonism with eritoran inhibited LPS-induced mRNA expression of IL-6, IL-8, TNFα, CCL-2, VCAM and ICAM (P<0.05 for all) and inhibited Ox-PAPC-induced mRNA expression of IL-8 (P<0.05) and IL-6, albeit not to a statistically significant level (p = 0.07). In contrast, eritoran did not affect FFA-induced mRNA expression of IL-6 (P>0.05). In 30 patients with RA (15 with the ag allele) undergoing measurement of FMD, no differences in FMD and plasma levels of IL-6, IL-8, VCAM, and ICAM were found between the aa and the ag phenotype (P>0.05 for all).<h4>Conclusions</h4>TLR4 signaling in endothelial cells may be triggered by LPS and oxidized phospholipids, leading to endothelial activation and inflammation, which are inhibited by eritoran. Our in vivo investigation, however, does not support an association between the Asp299Gly TLR4 polymorphism and improved endothelium-dependent vasodilator function in patients with RA. Further study is needed to better understand the potential role of TLR4 on endothelial dysfunction in this and other patient populations.
format	article
author	Rossella Menghini Umberto Campia Manfredi Tesauro Arianna Marino Valentina Rovella Giuseppe Rodia Francesca Schinzari Barbara Tolusso Nicola di Daniele Massimo Federici Angelo Zoli Gianfranco Ferraccioli Carmine Cardillo
author_facet	Rossella Menghini Umberto Campia Manfredi Tesauro Arianna Marino Valentina Rovella Giuseppe Rodia Francesca Schinzari Barbara Tolusso Nicola di Daniele Massimo Federici Angelo Zoli Gianfranco Ferraccioli Carmine Cardillo
author_sort	Rossella Menghini
title	Toll-like receptor 4 mediates endothelial cell activation through NF-κB but is not associated with endothelial dysfunction in patients with rheumatoid arthritis.
title_short	Toll-like receptor 4 mediates endothelial cell activation through NF-κB but is not associated with endothelial dysfunction in patients with rheumatoid arthritis.
title_full	Toll-like receptor 4 mediates endothelial cell activation through NF-κB but is not associated with endothelial dysfunction in patients with rheumatoid arthritis.
title_fullStr	Toll-like receptor 4 mediates endothelial cell activation through NF-κB but is not associated with endothelial dysfunction in patients with rheumatoid arthritis.
title_full_unstemmed	Toll-like receptor 4 mediates endothelial cell activation through NF-κB but is not associated with endothelial dysfunction in patients with rheumatoid arthritis.
title_sort	toll-like receptor 4 mediates endothelial cell activation through nf-κb but is not associated with endothelial dysfunction in patients with rheumatoid arthritis.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/7b64eb30c17443a592e3cd20aca7cb05
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Toll-like receptor 4 mediates endothelial cell activation through NF-κB but is not associated with endothelial dysfunction in patients with rheumatoid arthritis.

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