ESeroS-GS modulates lipopolysaccharide-induced macrophage activation by impairing the assembly of TLR-4 complexes in lipid rafts
ESeroS-GS modulates lipopolysaccharide-induced macrophage activation by impairing the assembly of TLR-4 complexes in lipid rafts
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DOI：
10.1016/j.bbamcr.2011.01.019
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发表时间：
2011-05-01
影响因子：
5.1
通讯作者：
Wei, Taotao
中科院分区：
文献类型：
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作者：
Duan, Wenjuan;Zhou, Juefei;Wei, Taotao
脂多糖 (LPS) 与巨噬细胞的结合会导致炎症反应。在极端情况下，它可能导致内毒素休克，常常导致死亡。包括生育酚在内的多种抗氧化剂可以降低体外和体内的 LPS 活性。为了阐明其作用的潜在机制，我们研究了 γ-L-谷氨酰-S-[2-[[[3,4-二氢-2,5,7,8-四甲基-2-(4,8,12-三甲基十三烷基)-2H-1-苯并吡喃-6-基]氧基]羰基]-3-[[2-(1H-吲哚-3-基)乙基]钠盐的作用[氨基]-3-氧代丙基]-L-半胱氨酰甘氨酸 (ESeroS-GS) 是一种新型 α-生育酚衍生物，可在体外和体内抑制 LPS 诱导的炎症。 ESeroS-GS以剂量依赖性方式减少RAW264.7巨噬细胞中TNF-α、IL-1β、IL-6和iNOS基因的转录，并抑制这些炎症因子的释放。此外，ESeroS-GS 还能抑制小鼠脓毒症模型中 LPS 诱导的死亡率。电泳迁移率变动分析 (EMSA) 和报告基因分析表明，ESeroS-GS 下调 NF-kappa B 的转录活性。通过分析细胞膜微域中 CD14 和 Toll 样受体 4 (TLR-4) 的分配，我们发现 ESeroS-GS 通过干扰 CD14 和 TLR-4 重新定位到脂质来减弱 LPS 与 RAW264.7 细胞的结合筏，阻断白细胞介素 1 受体相关激酶 1 (IRAK-1) 的激活，并抑制随后的 TAK1 和 IKK α/β 磷酸化，这共同导致了 NF-κ B 激活的抑制。综上所述，我们的数据表明 ESeroS-GS 可以通过脂筏依赖性机制损害 TLR-4 复合物组装来调节巨噬细胞中的 LPS 信号传导。 (C) 2011 Elsevier B.V. 保留所有权利。
The binding of lipopolysaccharides (LPS) to macrophages results in inflammatory responses. In extreme cases it can lead to endotoxic shock, often resulting in death. A broad range of antioxidants, including tocopherols, can reduce LPS activity in vitro and in vivo. To elucidate the underlying mechanisms of their action, we investigated the effect of the sodium salt of gamma-L-glutamyl-S-[2-[[[3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-2H-1-benzopyran-6-yl]oxy]carbonyl]-3-[[2-(1H-indol-3-yl)ethyl] amino]-3-oxopropyl]-L-cysteinylglycine (ESeroS-GS), a novel alpha-tocopherol derivative, on LPS-induced inflammation in vitro and in vivo. ESeroS-GS reduced the transcription of TNF-alpha, IL-1 beta, IL-6 and iNOS genes in a dose-dependent manner in RAW264.7 macrophages, and inhibited the release of these inflammatory factors. In addition, ESeroS-GS inhibited LPS-induced mortality in a mouse sepsis model. Electrophoretic mobility shift assays (EMSA) and reporter gene assays revealed that ESeroS-GS down-regulated the transcriptional activity of NF-kappa B. By analyzing the partitioning of CD14 and Toll-like receptor 4 (TLR-4) in cell membrane microdomains, we found that ESeroS-GS attenuates the binding of LPS to RAW264.7 cells via interfering with the relocation of CD14 and TLR-4 to lipid rafts, blocking the activation of interleukin-1 receptor-associated kinase 1 (IRAK-1), and inhibiting the consequent phosphorylation of TAK1 and IKK alpha/beta, which together account for the suppression of NF-kappa B activation. Taken together, our data suggest that ESeroS-GS can modulate LPS signaling in macrophages by impairing TLR-4 complex assembly via a lipid raft dependent mechanism. (C) 2011 Elsevier B.V. All rights reserved.