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

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-κB activity, 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.

• Authors: Sophie Van Linthout, Frank Spillmann, Gallia Graiani, Kapka Miteva, Jun Peng, Eline Van Craeyveld, Marco Meloni, Markus Tölle, Felicitas Escher, Aysun Subasigüller, Wolfram Doehner, Federico Quaini, Bart De Geest, Heinz-Peter Schultheiss, Carsten Tschöpe
• Journal: Journal of molecular medicine (Berlin, Germany) (J Mol Med (Berl)) Vol. 89 Issue 2 Pg. 151-60 (Feb 2011) ISSN: 1432-1440 [Electronic] Germany
• PMID: 20972769 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apolipoprotein A-I
• Lipopolysaccharides
• Lipoproteins, HDL
• Toll-Like Receptor 4

Topics

• Animals
• Apolipoprotein A-I (genetics, metabolism)
• Cell Line
• Down-Regulation
• Endothelial Cells (metabolism, pathology, physiology)
• Gene Expression Regulation
• Gene Transfer Techniques
• Humans
• Inflammation (chemically induced)
• Lipopolysaccharides
• Lipoproteins, HDL (metabolism)
• Lung (metabolism, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Signal Transduction
• Survival Analysis
• Toll-Like Receptor 4 (metabolism)