Advanced glycation end products (AGEs) synergistically potentiated the proinflammatory action of lipopolysaccharide (LPS) and high mobility group box-1 (HMGB1) through their direct interactions.
Advanced glycation end products (AGEs) synergistically potentiated the proinflammatory action of lipopolysaccharide (LPS) and high mobility group box-1 (HMGB1) through their direct interactions.
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晚期糖基化终产物 (AGE) 通过直接相互作用协同增强脂多糖 (LPS) 和高迁移率族蛋白 1 (HMGB1) 的促炎作用。
DOI：
10.1007/s11033-020-05783-y
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Mori S.
中科院分区：
文献类型：
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作者：
Watanabe M;Toyomura T;Tomiyama M;Wake H;Liu K;Teshigawara K;Takahashi H;Nishibori M;Mori S.
以前，我们发现，晚期糖基化终产物（AGEs）直接与肿瘤坏死因子（TNF）样细胞凋亡的弱诱导剂，一种控制炎症的细胞因子，这种相互作用抑制其作用。这一发现提出了AGEs通过直接相互作用改变其他细胞因子功能的新可能性。为了研究这种可能性，我们利用蛋白质芯片技术对AGEs进行了筛选，发现高迁移率族蛋白B1（HMGB 1）与AGEs具有显著的高亲和力。高迁移率族蛋白1（HMGB 1）是一种典型的促炎损伤相关分子模式，与脂多糖（lipopolysaccharide，LPS）直接作用，发挥其致炎作用。当LPS、HMGB 1和AGEs混合时，HMGB 1在非变性PAGE中的迁移率发生显著变化，表明这三种分子形成了三联体复合物。在LPS-HMGB 1混合物中加入AGEs可协同增强LPS-HMGB 1刺激的巨噬细胞样RAW264.7细胞中TNF-α mRNA的表达。此外，采用受体敲除克隆的方法，证实LPS-HMGB 1-AGEs复合物增强的促炎反应是通过Toll样受体4和AGEs受体介导的，提示AGEs通过直接相互作用增强LPS-HMGB 1刺激的促炎反应而发挥其病理生理作用。
Previously, we found that advanced glycation endproducts (AGEs) directly interact with tumor necrosis factor (TNF)-like weak inducer of apoptosis, a cytokine that controls inflammation, and that this interaction inhibited its action. This finding raised the novel possibility that AGEs alter the function of other cytokines through direct interaction. To investigate this possibility, we performed comprehensive screening for candidates that interacted with AGEs using protein array analysis. The array analysis revealed that high mobility group box-1 (HMGB1) had a markedly high affinity for AGEs. HMGB1 is a representative proinflammatory damage-associated molecular pattern molecule, and is reported to interact with lipopolysaccharide (LPS) directly to exert its inflammatory function. When LPS, HMGB1, and AGEs were mixed, the mobility of HMGB1 had shifted significantly in native PAGE, suggesting that these three molecules formed a triplet complex. The addition of AGEs to the LPS–HMGB1 mixture synergistically potentiated LPS–HMGB1-stimulated TNF-α mRNA expression in macrophage-like RAW264.7 cells. In addition, using receptor knockout clones, the increased proinflammatory response by LPS–HMGB1–AGEs complex was demonstrated to be mediated via Toll-like receptor 4 and receptor for AGEs. Taken together, this study suggested that AGEs carry out their pathophysiological roles by potentiating the LPS–HMGB1-stimulated proinflammatory response through direct interactions.