Down-regulation of endothelial TLR4 signalling after apo A-I gene transfer contributes to improved survival in an experimental model of lipopolysaccharide-induced inflammation

Van Linthout, S. et al. (2011) Down-regulation of endothelial TLR4 signalling after apo A-I gene transfer contributes to improved survival in an experimental model of lipopolysaccharide-induced inflammation. Journal of Molecular Medicine, 89(2), pp. 151-160. (doi: 10.1007/s00109-010-0690-6)

Abstract

The protective effects of high-density lipoprotein (HDL) under lipopolysaccharide (LPS) conditions have been well documented. Here, we investigated whether an effect of HDL on Toll-like receptor 4 (TLR4) expression and signalling may contribute to its endothelial-protective effects and to improved survival in a mouse model of LPS-induced inflammation and lethality. HDL cholesterol increased 1.7-fold (p < 0.005) and lung endothelial TLR4 expression decreased 8.4-fold (p < 0.005) 2 weeks after apolipoprotein (apo) A-I gene transfer. Following LPS administration in apo A-I gene transfer mice, lung TLR4 and lung MyD88 mRNA expression, reflecting TLR4 signalling, were 3.0-fold (p < 0.05) and 2.1-fold (p < 0.05) lower, respectively, than in LPS control mice. Concomitantly, LPS-induced lung neutrophil infiltration, lung oedema and mortality were significantly attenuated following apo A–I transfer. In vitro, supplementation of HDL or apo A–I to human microvascular endothelial cells-1 24 h before LPS administration reduced TLR4 expression, as assessed by fluorescent-activated cell sorting, and decreased the LPS-induced MyD88 mRNA expression and NF-κBactivity, independently of LPS binding. In conclusion, HDL reduces TLR4 expression and signalling in endothelial cells, which may contribute significantly to the protective effects of HDL in LPS-induced inflammation and lethality.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Meloni, Dr Marco
• Authors: Van Linthout, S., Spillmann, F., Graiani, G., Miteva, K., Peng, J., Van Craeyveld, E., Meloni, M., Tölle, M., Escher, F., Subasigüller, A., Doehner, W., Quaini, F., De Geest, B., Schultheiss, H.-P., and Tschöpe, C.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: Journal of Molecular Medicine
• Publisher: Springer Verlag
• ISSN: 0946-2716
• ISSN (Online): 1432-1440
• Copyright Holders: Copyright © 2014 The Authors
• First Published: First published in Journal of Molecular Medicine 89(2):151-160
• Publisher Policy: Reproduced under a Creative Commons License