Pathophysiological role of S100A12 protein via the receptor for advanced glycation end products(EN-RAGE)
| Project/Area Number |
13671203
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Metabolomics
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| Research Institution | Kansai Medical University |
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Principal Investigator |
KOSAKI Atsushi Kansai Medical University, Faculty of Medicine, Assistant Professor, 医学部, 講師 (40330188)
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| Project Period (FY) |
2001 – 2002
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| Project Status |
Completed (Fiscal Year 2002)
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| Budget Amount *help |
¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 2002: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2001: ¥2,600,000 (Direct Cost: ¥2,600,000)
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| Keywords | S100A12 / RAGE / Macrophages / IL-6 / PPAR / Diabetes mellitus / チアゾリジン / PPARγ |
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| Research Abstract |
1.The Regulation of EN-RAGE(S100A12) Gene Expression in Human THP-1 Macrophages
EN-RAGE is a ligand for the receptor for advanced glycation end products(RAGE) and may be involved in the development of diabetic macro-and micro-angiopathy. This study is designed to investigate the regulation of EN-RAGE gene expression in human macrophages. The amounts of EN-RAGE mRNA were measured in cultured human THP-1 macrophages after treatment with various stimuli known to modulate atherosclerosis. First, interleukin-6(IL-6), a proinflammatory cytokine, increased the level of EN-RAGE mRNA by〜2-fold in a time-and a dose-dependent fashion. EN-RAGE protein was detected in the cultured medium and increased significantly by the addition of IL-6. The induction was abolished by pretreatment with the Jak kinase inhibitor and cycloheximide, but not with the MEK kinase inhibitor. Second, pioglitazone, a thiazolidinedione, decreased the level of EN-RAGE mRNA by〜25% of the basal in a time-and a dose-dependent fa
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shion. Pioglitazone also inhibited the induction of EN-RAGE mRNA by IL-6. These results indicate the production of EN-RAGE is induced by IL-6 through de novo protein synthesis via the JAK-STAT kinase pathway and inhibited by the activation of peroxisome proliferator activated receptor-γ(PPARγ) in human macrophages.
2.Increased plasma S100A12(EN-RAGE) levels in patients with type 2 diabetes
S100A12, also called EN-RAGE or CAAF1, is a ligand for the receptor for advanced glycation end products(RAGE). It has been shown that S100A12 induces adhesion molecules such as VCAM-1 and ICAM-1 in the vascular endothelial cell and mediates migration and activation of monocytes/macrophages through RAGE binding, and that infusion of lipopolysaccharide(LPS) into mice causes time-dependent increase of S100A12 in the plasma. Therefore, circulating S100A12 protein may be involved in chronic inflammation in the atherosclerotic lesion. In this study, we developed an ELISA system which uses specific monoclonal antibodies against recombinant human S100A12 to measure plasma S100A12 levels in patients with diabetes. On using our S100A12 ELISA assay system, concentrations of plasma S100A12 were more than twice as high in the patients with diabetes compared to those without. Using univariate analysis in all subjects, plasma S100A12 concentrations correlated with HbA1c, fasting glucose, high sensitivity CRP and white blood cell count. Step-wise multiple regression analyses, however, revealed that only white blood cell count and HbA1c remained significant independent determinants of plasma S100A12 concentration. These results suggest that plasma S100A12 protein levels are regulated by factors related to subclinical inflammation and glucose control in patients with type 2 diabetes. Less
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(3 results)
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[Publications] Hasegawa T, Kosaki A, Kimura T, Matsubara H, Mori Y, Okigaki M, Masaki H, Toyoda N, Inoue-Shibata M, Kimura Y, Nishikawa M, Iwasaka T.: "The Regulation of EN-RAGE(S100A12) Gene Expression in Human THP-1 Macrophages."Atherosclerosis. 171. 211-218 (2003)
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