Advanced Glycation End Products Subspecies-Selectively Induce Adhesion Molecule Expression and Cytokine Production in Human Peripheral Blood Mononuclear Cells
Advanced Glycation End Products Subspecies-Selectively Induce Adhesion Molecule Expression and Cytokine Production in Human Peripheral Blood Mononuclear Cells
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DOI：
10.1124/jpet.109.150581
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发表时间：
2009-07-01
影响因子：
3.5
通讯作者：
Nishibori, Masahiro
中科院分区：
文献类型：
--
作者：
Takahashi, Hideo Kohka;Mori, Shuji;Nishibori, Masahiro
晚期糖基化终产物（AGEs）是暴露于各种还原糖后成为糖基化的蛋白质或脂质。AGEs的积累可诱发糖尿病并发症。微炎症是糖尿病血管并发症常见的主要发病机制。单核/巨噬细胞和T细胞的激活在动脉粥样硬化的发病机制中起作用。T细胞的活化需要单核细胞上黏附分子的表达增强。AGEs通过参与AGE受体（RAGE）激活单核细胞；然而，关于不同AGE部分对单核细胞的激动剂活性的概况知之甚少。我们研究了四种不同的AGE亚型（AGE修饰的牛血清白蛋白；AGE-2, AGE-3， AGE-4和AGE-5）在0.1至100 μ g/ml浓度范围内对单核细胞细胞间粘附分子-1，B7.1, B7.2和CD40表达的影响及其对人外周血单核细胞中干扰素γ和肿瘤坏死因子α产生的影响。在所检测的AGEs中，AGE-2和AGE-3选择性地诱导粘附分子表达和细胞因子产生。使用抗粘附分子抗体的拮抗实验表明，单核细胞与T/自然杀伤细胞之间的细胞间相互作用参与了age -2和age -3诱导的细胞因子的产生。AGE-2和AGE-3上调RAGE在单核细胞上的表达。核因子κ B和p38丝裂原活化蛋白激酶抑制剂可抑制AGE-2和AGE-3的作用。这些结果表明AGE-2和AGE-3通过RAGE激活单核细胞，导致粘附分子表达和细胞因子产生上调。
Advanced glycation end products (AGEs) are proteins or lipids that become glycated after exposure to diverse reducing sugars. Accumulation of AGEs induces diabetes complications. Microinflammation is a common major mechanism in the pathogenesis of diabetic vascular complications. Activation of monocytes/macrophages and T cells plays roles in the pathogenesis of atherosclerosis. The activation of T cells requires the enhanced expression of adhesion molecules on monocytes. AGEs activate monocytes by engaging the receptor for AGE (RAGE); however, little is known about the profile of agonist activity of diverse AGE moieties on monocytes. We investigated the effect of four distinct AGE subtypes (AGE-modified bovine serum albumin; AGE-2, AGE-3, AGE-4, and AGE-5) at concentrations ranging from 0.1 to 100 mu g/ml on the expression of intercellular adhesion molecule-1, B7.1, B7.2, and CD40 on monocytes and its impact on the production of interferon-gamma and tumor necrosis factor-alpha in human peripheral blood mononuclear cells. Among the AGEs examined, AGE-2 and AGE-3 selectively induced adhesion molecule expression and cytokine production. Antagonism experiments using antibodies against adhesion molecules demonstrated that cell-to-cell interaction between monocytes and T/natural killer cells was involved in AGE-2-and AGE-3-induced cytokine production. AGE-2 and AGE-3 up-regulated the expression of RAGE on monocytes. The effects of AGE-2 and AGE-3 were inhibited by nuclear factor-kappa B and p38 mitogen-activated protein kinase inhibitors. These results indicated that AGE-2 and AGE-3 activated monocytes via RAGE, leading to the up-regulation of adhesion molecule expression and cytokine production.