C-reactive protein (CRP) up-regulates expression of receptor for advanced glycation end products (RAGE) and its inflammatory ligand EN-RAGE in THP-1 cells: inhibitory effects of atorvastatin.
BACKGROUND
Receptor for advanced glycation end products (RAGE) may play an important role in inflammatory processes and endothelial activation. Extracellular newly identified RAGE binding protein (EN-RAGE), natural pro-inflammatory ligand for RAGE. The role of C-reactive protein (CRP) as a mediator in inflammation and atherosclerosis is the subject of recent investigations worldwide. In the present study, we investigated the effect of CRP on RAGE and EN-RAGE gene expression in THP-1 monocytic cell line. MAP kinases (ERK, p38 and JNK) were exploited as possible signaling pathways involved in the signal transduction by CRP. Further, atorvastatin was used as a therapeutic modality for modulation of these genes in the presence of CRP.


METHODS
Time and dose-dependent experiments were carried out in the presence of CRP. Specific MAPK pathways inhibitors were used to elucidate the signaling pathways involved. Effect of atorvastatin was also determined in the presence of CRP on the expression of these genes.


RESULTS
Time and dose-dependent experiments revealed that, treatment of THP-1 cells with 100 microg of CRP/ml/10(6) cells for 24 h, augmented the expression of RAGE and EN-RAGE genes by 2.5-3.5 folds and 3.5-4.5 folds respectively. CRP acted via FcgammaRII and utilized ERK, p38 and JNK pathways to transduce signals. Atorvastatin in a dose of 20 muM, was able to attenuate up-regulation of CRP-induced genes (p<0.01) and effects were both dose and time-dependent.


CONCLUSIONS
Our data strongly suggests that blockade of RAGE-EN-RAGE by statins at an early stage may prevent inflammation in atherosclerosis and counteract the harmful effects mediated by CRP.
Mahajan
Nitin
N
Department of Experimental Medicine & Biotechnology, Postgraduate Institute of Medical Education & Research, Chandigarh 160012, India.
Bahl
Ajay
A
Dhawan
Veena
V
D000069059:Atorvastatin; D002097:C-Reactive Protein / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology; D009000:Monocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D011758:Pyrroles / Q000494:pharmacology*; D000067759:Receptor for Advanced Glycation End Products; D017452:Receptors, IgG / Q000378:metabolism; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D009418:S100 Proteins / Q000235:genetics / Q000378:metabolism*; D000067616:S100A12 Protein; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D017127:Glycation End Products, Advanced; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D000067759:Receptor for Advanced Glycation End Products; D017452:Receptors, IgG; D011971:Receptors, Immunologic; D009418:S100 Proteins; D000067616:S100A12 Protein; C090441:S100A12 protein, human; D002097:C-Reactive Protein; D000069059:Atorvastatin; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases