Lipid rafts regulate ethanol-induced activation of TLR4 signaling in murine macrophages
Lipid rafts regulate ethanol-induced activation of TLR4 signaling in murine macrophages
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DOI：
10.1016/j.molimm.2007.10.025
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发表时间：
2008-04-01
影响因子：
3.6
通讯作者：
Guerri, Consuelo
中科院分区：
文献类型：
--
作者：
Fernandez-Lizarbe, Sara;Pascual, Maria;Guerri, Consuelo
Toll样受体(Toll-like Receptor，TLRs)反应在先天抵抗感染中起关键作用。研究表明，饮酒可以抑制TLR4介导的炎症反应，下调炎性细胞因子的产生。我们最近报道，低浓度的乙醇激活星形胶质细胞中的TLR4信号，并引发神经炎症。由于巨噬细胞是天然免疫中的重要细胞，我们研究了低浓度乙醇是否能刺激小鼠RAW 264.7巨噬细胞TLR4的信号反应，并探讨了乙醇诱导TLR4激活的机制。我们的结果表明，在高浓度(100 MM)的乙醇或在有内毒素存在的情况下，乙醇抑制TLR4的反应，而低到中等浓度(10-50 mM)的乙醇激活TLR4的反应，并触发丝裂原激活蛋白激酶(MAPKs)和转录因子NF-kappa B途径的刺激，导致一氧化氮(NO)和炎性细胞因子的产生。用抗TLR4抗体预处理可消除乙醇对细胞因子产生的影响。我们还提供了用乙醇或脂多糖刺激诱导TLR4和信号分子(IRAK和MAPKs)移位和聚集到脂筏中的证据。用脂筏干扰剂链溶素-O或皂苷处理，可取消乙醇诱导的TLR4/IL-1RI信号通路的激活。综上所述，本研究结果表明，中低浓度乙醇能够刺激TLR4/IL-1RI反应，并为乙醇通过与膜筏相互作用促进TLR4/IL-1RI募集和信号传导提供了新的机制证据。(C)2007爱思唯尔有限公司。保留所有权利。
Toll-like receptors (TLRs) response is critical in innate resistance to infection. Alcohol consumption has been shown to suppress the inflammatory response mediated through TLR4, down regulating the production of inflammatory cytokines. We recently reported that low concentrations of ethanol activate TLR4 signaling in astrocytes and triggers neuroinflammation. Because macrophages are important cells in innate immunity, we investigate whether low concentrations of ethanol could stimulate the TLR4 signaling response in murine RAW 264.7 macrophages, and the mechanism involved in the ethanol-induced TLR4 activation. Our results show that while ethanol, at high concentrations (100 mM) or in the presence of the LPS, suppresses the TLR4 response, low to moderate levels (10-50 mM) activate the TLR4 response and triggers the stimulation of the mitogen-activated protein kinases (MAPKs) and the transcription factor NF-kappa B pathways, leading to the production of nitric oxide (NO) and inflammatory cytokines. Pre-treatment with anti-TLR4 Abs abolishes the effects of ethanol on the production of cytokines. We also present evidence that stimulation with either ethanol or LPS induces translocation and clustering of TLR4 and signaling molecules (IRAK and MAPKs) into lipid rafts. Treatment with either streptolysin-O or saponin, lipid rafts disrupting agents, abolishes the ethanol-induced activation of the TLR4/IL-1RI signaling pathway. In summary, the present results demonstrate that low to moderate concentrations of ethanol are capable of stimulating TLR4/IL-1RI response, and provide evidence of a novel mechanism by which ethanol, through its interaction with membrane rafts, can promote TLR4/IL-1RI recruitment and signaling. (C) 2007 Elsevier Ltd. All rights reserved.