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Diabetologia. 2004 May;47(5):844-52. Epub 2004 May 1.

Binding of receptor for advanced glycation end products (RAGE) ligands is not sufficient to induce inflammatory signals: lack of activity of endotoxin-free albumin-derived advanced glycation end products.

Author information

1
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.

Abstract

AIMS/HYPOTHESIS:

Activation of the receptor for advanced glycation end products (RAGE) reportedly triggers cellular responses implicated in the pathogenesis of diabetes, such as increasing vascular cell adhesion molecule-1 (VCAM-1) expression on vascular endothelial cells and inducing TNF-alpha secretion by mononuclear cells. The objective of this study was to evaluate whether RAGE binding affinity of AGE-BSAs and cellular activation correlate.

METHODS:

To produce AGEs with varying glycation, bovine albumin AGEs were prepared with 500 mmol/l of glucose, fructose or ribose at times of incubation from 1 to 12 weeks. In addition, AGE-BSA was generated using either glyoxylic acid or glycolaldehyde. Cellular binding of the AGE-BSAs and the effect on endothelial cell VCAM-1 expression were studied in RAGE-expressing human microvascular endothelial cell line-4 cells. Induction of TNF-alpha secretion was assessed using RAGE-expressing human peripheral blood mononuclear cells (PBMCs).

RESULTS:

Cellular binding of the different AGE preparations correlated well with RAGE affinity. Interestingly, we found that the AGE preparations, which were essentially endotoxin free (< or =0.2 ng/mg protein), were incapable of inducing VCAM-1 or TNF-alpha secretion regardless of RAGE binding affinity, AGE concentration or incubation time. In contrast, the reported RAGE ligand S100b was confirmed to induce VCAM-1 expression on endothelial cells and TNF-alpha secretion by PBMCs after 24 h of treatment.

CONCLUSIONS/INTERPRETATION:

The results of this study suggest that AGE modification and high RAGE binding affinity are not sufficient to generate pro-inflammatory signalling molecules. Thus, RAGE binding affinity of AGE-BSAs does not seem to correlate with cellular activation. Our findings using AGEs with strong RAGE-binding properties indicate that AGEs may not uniformly play a role in cellular activation.

PMID:
15127201
DOI:
10.1007/s00125-004-1392-9
[Indexed for MEDLINE]

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