Pathophysiological role of S100A12 protein via the receptor for advanced glycation end products(EN-RAGE)

1.enrage （S100A12）基因在人THP-1巨噬细胞中的表达调控gesen -RAGE是晚期糖基化终产物（RAGE）受体的配体，可能参与糖尿病大血管和微血管病变的发展。本研究旨在探讨EN-RAGE基因在人巨噬细胞中的表达调控。在接受各种已知可调节动脉粥样硬化的刺激后，在培养的人THP-1巨噬细胞中测量EN-RAGE mRNA的量。首先，白细胞介素-6(IL-6)，一种促炎细胞因子，以时间和剂量依赖的方式将EN-RAGE mRNA的水平提高了约2倍。在培养基中检测到EN-RAGE蛋白，并通过添加IL-6显著增加。Jak激酶抑制剂和环己亚胺预处理可以消除诱导作用，而MEK激酶抑制剂则不能。其次，吡格列酮，一种噻唑烷二酮，在一个时间和剂量依赖性的过程中，使EN-RAGE mRNA水平降低了25%的基础水平。吡格列酮还能抑制IL-6对EN-RAGE mRNA的诱导。这些结果表明，在人巨噬细胞中，IL-6通过JAK-STAT激酶途径的从头蛋白合成诱导EN-RAGE的产生，并被过氧化物酶体增殖物激活受体-γ(PPARγ)的激活所抑制。2型糖尿病患者血浆S100A12（EN-RAGE）水平升高ess100a12，也称为EN-RAGE或CAAF1，是晚期糖基化终产物（RAGE）受体的配体。研究表明，S100A12在血管内皮细胞中诱导VCAM-1、ICAM-1等粘附分子，并通过RAGE结合介导单核/巨噬细胞的迁移和活化，脂多糖（LPS）注入小鼠可引起血浆中S100A12的时间依赖性增加。因此，循环中的S100A12蛋白可能参与了动脉粥样硬化病变的慢性炎症。在这项研究中，我们开发了一种ELISA系统，该系统使用针对重组人S100A12的特异性单克隆抗体来检测糖尿病患者血浆中S100A12的水平。在使用我们的S100A12 ELISA检测系统时，糖尿病患者的血浆S100A12浓度是非糖尿病患者的两倍多。对所有受试者进行单因素分析，血浆S100A12浓度与HbA1c、空腹血糖、高敏CRP和白细胞计数相关。然而，逐步多元回归分析显示，只有白细胞计数和HbA1c仍然是血浆S100A12浓度的重要独立决定因素。这些结果表明血浆S100A12蛋白水平受2型糖尿病患者亚临床炎症和血糖控制相关因素的调节。少

1.The Regulation of EN-RAGE(S100A12) Gene Expression in Human THP-1 MacrophagesEN-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 … More 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 diabetesS100A12, 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