Divergent pathways of gene expression are activated by the RAGE ligands S100b and AGE-BSA.
Activation of the receptor for advanced glycation end products (RAGE) reportedly triggers a variety of proinflammatory responses. However, our previous work revealed that RAGE-binding AGEs free of endotoxin were incapable of inducing vascular cell adhesion molecule-1 (VCAM-1) or tumor necrosis factor-alpha (TNF-alpha) expression. Thus, the objective of this study was to clarify the role of AGEs in cell activation through gene expression profiling using both in vitro and in vivo model systems. Endothelial cells treated with AGE-BSA, previously shown to bind RAGE with high affinity, did not show gene expression changes indicative of an inflammatory response. In contrast, the alternate RAGE ligand, S100b, triggered an increase in endothelial mRNA expression of a variety of immune-related genes. The effects of AGEs were studied in vivo using healthy mice exposed to two different treatment conditions: 1) intravenous injection of a single dose of model AGEs or 2) four intraperitoneal injections of model AGEs (once per day). In both cases, the liver was extracted for gene expression profiling. Both of the short-term AGE treatments resulted in a moderate increase in liver mRNA levels for genes involved in macrophage-based clearance/detoxification of foreign agents. Our findings using AGEs with strong RAGE-binding properties indicate that AGEs may not uniformly play a role in cellular activation.
Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
Jessica V
JV
Valencia
Manisha
M
Mone
Jin
J
Zhang
Marla
M
Weetall
Frank P
FP
Buxton
Thomas E
TE
Hughes
D000818:Animals; D001324:Autoantigens / Q000235:genetics; D002417:Cattle; D004798:Enzymes / Q000235:genetics; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000502:physiology*; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D008099:Liver / Q000502:physiology; D051379:Mice; D009414:Nerve Growth Factors / Q000235:genetics*; D011506:Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000235:genetics*; D012710:Serum Albumin, Bovine / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics
D001324:Autoantigens; D004798:Enzymes; D017127:Glycation End Products, Advanced; D009414:Nerve Growth Factors; D011506:Proteins; D012333:RNA, Messenger; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; C579159:S100b protein, mouse; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D012710:Serum Albumin, Bovine