RAGE-Dependent Regulation of Calcium-Binding Proteins S100A8 and S100A9 in Human THP-1

Abstract

Proinflammatory cell activation via the receptor for advanced glycation end products (RAGE) pathway may play a central pathogenetic role in atherosclerosis. Since S100A8/A9 was recently identified as ligand of RAGE, we determined the effects of proinflammatory cytokines on RAGE-mediated induction of gene expression of S100A8 and S100A9. mRNA levels of S100A8 and S100A9 were upregulated following cytokine stimulation with IL-6 (1, 10, 100 ng/ml) or TNFα (10 ng/ml) in human THP-1 cells. Preincubation of cells with 2000 ng/ml AGE (advanced glycation end products) before cytokine stimulation resulted in upregulation of RAGE. Pretreatment of THP-1 with AGE followed by stimulation with IL-6 (10 ng/ml) or TNFα (10 ng/ml) further increased S100A8 and S100A9 mRNA expression and S100A8/A9 release into cell culture supernatant, as compared to pretreatment with non-glycated albumin as control. Binding of AGE to RAGE was blocked with a neutralizing anti-RAGE antibody. Normal mouse IgG served as control. Cytokine-stimulated induction of S100A8 and S100A9 mRNA levels as well as of S100A8/A9 release after preincubation of cells with AGE were significantly suppressed by RAGE blockade, indicating a RAGE-dependent pathway of AGE-mediated S100A8/A9 expression.The cytokine-induced potentiated S100A8 and S100A9 expression under conditions with a high AGE burden is able to aggravate proinflammatory conditions via activation of the RAGE pathway.

S100 proteins - glycation/AGE - RAGE - inflammation - diabetes

References

• 1 Basta G, De Caterina R. Advanced glycation end products and vascular inflammation: implications for accelerated atherosclerosis in diabetes.  Cardiovasc Res. 2004;  63 (4) 582-592
• 2 Basta G, Lazzerini G, Massaro M. et al . Advanced glycation end products activate endothelium through signal-transduction receptor RAGE: a mechanism for amplification of inflammatory responses.  Circulation. 2002;  105 816-822
• 3 Bierhaus A, Chevion S, Chevion M. et al . Advanced glycation end product-induced activation of NF-kappaB is suppressed by alpha-lipoic acid in cultured endothelial cells.  Diabetes. 1997a;  46 1438-1490
• 4 Bierhaus A, Hofmann MA, Ziegler R. et al . AGEs and their interaction with AGE-receptors in vascular disease and diabetes mellitus. I. The AGE concept.  Cardiovasc Res. 1998;  37 (3) 586-600
• 5 Bierhaus A, Illmer T, Kasper M. et al . Advanced glycation end product (AGE)-mediated induction of tissue factor in cultured endothelial cells is dependent on RAGE.  Circulation. 1997b;  96 2262-2271
• 6 Boyd JH, Kan B, Roberts H. et al . S100A8 and S100A9 mediate endotoxin-induced cardiomyocyte dysfunction via the receptor for advanced glycation end products.  Circ Res. 2008;  102 (10) 1239-1246
• 7 Cai W, He JC, Zhu L. et al . High levels of dietary advanced glycation end products transform low-density lipoprotein into a potent redox-sensitive mitogen-activated protein kinase stimulant in diabetic patients.  Circulation. 2004;  110 285-291
• 8 Ehlermann P, Eggers K, Bierhaus A. et al . Increased proinflammatory endothelial response to S100A8/A9 after preactivation through advanced glycation end products.  Cardiovasc Diabetol. 2006;  5 6-14
• 9 Hofmann MA, Drury S, Fu C. et al . RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides.  Cell. 1999;  97 889-901
• 10 Huttunen HJ, Kuja-Panula J, Sorci G. et al . Coregulation of neurite outgrowth and cell survival by amphoterin and S100 proteins through receptor for advanced glycation end products (RAGE) activation.  J Biol Chem. 2000;  275 40096-40105
• 11 Libby P. Role of inflammation in atherosclerosis associated with rheumatoid arthritis.  Am J Med. 2008;  121 (10 Suppl 1) 21-31
• 12 McCormick MM, Rahimi F, Bobryshev YV. et al . S100A8 and S100A9 in human arterial wall: Implications for atherogenesis.  J Biol Chem. 2005;  280 (50) 41521-41529
• 13 Miyamoto S, Ueda M, Ikemoto M. et al . Increased serum levels and expression of S100A8/A9 complex in infiltrated neutrophils in atherosclerotic plaque of unstable angina.  Heart. 2008;  94 (8) 1002-1007
• 14 Morrow DA. Myeloid-related protein 8/14 and the risk of cardiovascular death or myocardial infarction after an acute coronary syndrome in the Pravastatin or Atorvastatin Evaluation and Infection Therapy: Thrombolysis in Myocardial Infarction (PROVE IT-TIMI 22) trial.  Am Heart J. 2008;  155 (1) 49-55
• 15 Park L, Raman KG, Lee KJ. et al . Suppression of accelerated diabetic atherosclerosis by the soluble receptor for advanced glycation endproducts.  Nat Med. 1998;  4 1025-1031
• 16 Rammes A, Roth J, Goebeler M. et al . Myeloid-related protein (MRP) 8 and MRP14, calcium-binding proteins of the S100 family, are secreted by activated monocytes via a novel, tubulin-dependent pathway.  J Biol Chem. 1997;  272 9496-9502
• 17 Ross R. Atherosclerosis – an inflammatory disease.  N Engl J Med. 1999;  340 115-126
• 18 Roth J, Goebeler M, Sorg C. S100A8 and S100A9 in inflammatory diseases.  Lancet. 2001;  357 1041
• 19 Roth J, Goebeler M, Wrocklage V. et al . Expression of the calcium-binding proteins MRP8 and MRP14 in monocytes is regulated by a calcium-induced suppressor mechanism.  Biochem J. 1994;  301 655-660
• 20 Saadeddin SM, Habbab MA, Ferns GA. Markers of inflammation and coronary artery disease.  Med Sci Monit. 2002;  8 (1) RA5-RA12
• 21 Schmidt AM, Yan SD, Yan SF. et al . The biology of the receptor for advanced glycation end products and its ligands.  Biochim Biophys Acta. 2000;  1498 99-111
• 22 Soro-Paavonen A, Watson AM, Li J. et al . Receptor for advanced glycation end products (RAGE) deficiency attenuates the development of atherosclerosis in diabetes.  Diabetes. 2008;  57 (9) 2461-2469
• 23 Vlassara H. The AGE-receptor in the pathogenesis of diabetic complications.  Diabetes Metab Res Rev. 2001;  17 (6) 436-443
• 24 Yeh CH, Sturgis L, Haidacher J. et al . Requirement for p38 and p44/p42 mitogen-activated protein kinases in RAGE-mediated nuclear factor-kappaB transcriptional activation and cytokine secretion.  Diabetes. 2001;  50 1495-1504

Correspondence