Activation of receptors for advanced glycation endproducts (RAGEs) in human monocytes
Ivanova, Nina Mihaylova
LicenseStandard (Fassung vom 03.05.2003)
In conditions of hyperglycemia and hyperlipidemia formation of advanced glycation endproducts (AGEs) is elevated. The receptor for AGEs (RAGE) is highly expressed on endothelium and monocytes in patients with diabetes mellitus, which have increased level of pro-inflammatory cytokines in blood, correlating with high risk of development of atherosclerosis. The regulation of RAGE expression may be an important factor for AGE deleterious consequences, but to date little is known about such mechanisms in human monocytes. The present study investigated whether activation of RAGEs in human monocytes might stimulate the secretion of pro-inflammatory cytokines, which then in turn may increase cellular RAGE expression. Stimulation of freshly isolated human monocytes with AGEs or the RAGE activator S100 increased IL-6 and TNF-a protein secretion in a time- and concentration-dependent manner. This increase in cytokine protein release was due to an increase in IL-6 and TNF-a mRNA synthesis. In addition, from these two cytokines only TNF-a enhanced RAGE protein expression. This effect of TNF-a was due to RAGE gene activation, by activation of NF-kappa B transcription factor and its binding to proximal and distal NF-kappa B responsive elements in RAGE promoter. Finally, increased monocyte RAGE expression by pre-treatment with TNF-a enhances S100-induced IL-6 release. Thus, RAGE activation induces the expression of pro-inflammatory cytokines IL-6 and TNF-a in human monocytes. In turn, TNF-a enhance monocyte RAGE expression, thus increasing cell susceptibility towards pro-inflammatory RAGE activators’ effects. AGEs and other RAGE ligands are chemotactic agents for human blood monocyte. The current study investigates amyloid-ß peptide as a chemoattractant for human monocytes in vitro and suggests that amyloid-ß peptide mediated migration involves pertussis toxin sensitive G-proteins, Tyr-protein kinases, recruitment of PI3-kinase and activation of MAPK kinases.
Subject HeadingsGlykation [GND]
Amyloid beta-protein [MeSH]
Knee injuries [MeSH]