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

MedStar author(s):
Citation: PLoS ONE [Electronic Resource]. 9(6):e99053, 2014.PMID: 24918924Institution: MedStar Heart & Vascular InstituteForm of publication: Journal ArticleMedline article type(s): Journal Article | Research Support, Non-U.S. Gov'tSubject headings: *Arthritis, Rheumatoid/pp [Physiopathology] | *Endothelium, Vascular/ph [Physiology] | *NF-kappa B/me [Metabolism] | *Toll-Like Receptor 4/ph [Physiology] | Aorta/de [Drug Effects] | Aorta/ph [Physiology] | Cells, Cultured | Disaccharides/pd [Pharmacology] | Endothelium, Vascular/de [Drug Effects] | Humans | Lipopolysaccharides/ai [Antagonists & Inhibitors] | Phosphorylation | Sugar Phosphates/pd [Pharmacology]Year: 2014Local holdings: Available online through MWHC library: 2006 - presentISSN:
  • 1932-6203
Name of journal: PloS oneAbstract: CONCLUSIONS: 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.METHODS: 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).OBJECTIVE: 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).RESULTS: In HAEC, TLR4 antagonism with eritoran inhibited LPS-induced mRNA expression of IL-6, IL-8, TNFalpha, 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).All authors: Campia U, Cardillo C, di Daniele N, Federici M, Ferraccioli G, Marino A, Menghini R, Rodia G, Rovella V, Schinzari F, Tesauro M, Tolusso B, Zoli AFiscal year: FY2015Digital Object Identifier: Date added to catalog: 2015-03-17
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Item type Current library Collection Call number Status Date due Barcode
Journal Article MedStar Authors Catalog Article 24918924 Available 24918924

Available online through MWHC library: 2006 - present

CONCLUSIONS: 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.

METHODS: 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).

OBJECTIVE: 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).

RESULTS: In HAEC, TLR4 antagonism with eritoran inhibited LPS-induced mRNA expression of IL-6, IL-8, TNFalpha, 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).

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