Propofol inhibits lipoteichoic acid-induced iNOS gene expression in macrophages possibly through downregulation of toll-like receptor 2-mediated activation of Raf-MEK1/2-ERK1/2-IKK-NFκB
Propofol inhibits lipoteichoic acid-induced iNOS gene expression in macrophages possibly through downregulation of toll-like receptor 2-mediated activation of Raf-MEK1/2-ERK1/2-IKK-NFκB
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DOI：
10.1016/j.cbi.2009.06.011
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发表时间：
2009-10-30
影响因子：
5.1
通讯作者：
Chen, Ruei-Ming
中科院分区：
文献类型：
--
作者：
Chiu, Wen-Ta;Lin, Yi-Ling;Chen, Ruei-Ming
我们以前的研究表明，异丙酚抑制革兰氏阴性菌LPS诱导的NO生物合成。脂磷壁酸（LTA）是革兰氏阳性菌的外膜成分，可诱导感染性休克。本研究进一步探讨异丙酚对LTA诱导的巨噬细胞iNOS基因表达的影响及其可能的分子机制。暴露于LTA的巨噬细胞的亚硝酸盐和细胞内活性氧的产生增加，但丙泊酚减少这种增强的浓度和时间依赖性的方式。用LTA诱导的iNOS mRNA和蛋白质产生处理巨噬细胞。同时，丙泊酚在临床相关浓度为50 μ M显着抑制LTA引起的iNOS mRNA和蛋白质合成的增加。同时，暴露于LTA增加了核因子-κ B（NF κ B）从细胞质向细胞核的易位。异丙酚在50 μ M减少这种易位。电泳迁移率改变和报告基因分析进一步表明，丙泊酚可以减轻LTA诱导的NF κ B B的反式激活。丙泊酚依次降低LTA刺激的巨噬细胞中IKK、ERK 1/2、MEK 1/2和Raf的磷酸化。Toll样受体2（TLR 2）小干扰（si）RNA的应用降低了LTA刺激的巨噬细胞中该受体的翻译和Raf磷酸化。丙泊酚和TLR 2 siRNA的联合治疗协同改善了LTA诱导的iNOS mRNA表达和亚硝酸盐的产生。因此，本研究表明，异丙酚可以通过抑制iNOS基因表达下调NO的生物合成。其抑制机制可能是通过减少TLR 2介导的Raf-MEK 1/2-ERK 1/2-IKK-NF κ B的顺序激活而发生的。(C)2009爱思唯尔爱尔兰有限公司保留所有权利。
Our previous study showed that propofol suppressed Gram-negative bacterial LPS-induced NO biosynthesis. Lipoteichoic acid (LTA), an outer membrane component of Gram-positive bacteria, can induce septic shock. This study was further aimed to evaluate the effects of propofol on LTA-induced iNOS gene expression in macrophages and its possible molecular mechanisms. Exposure of macrophages to LTA increased production of nitrite and intracellular reactive oxygen species, but propofol reduced such enhancements in concentration- and time-dependent manners. Treatment of macrophages with LTA-induced iNOS mRNA and protein productions. Meanwhile, propofol at a clinically relevant concentration of 50 mu M significantly inhibited LTA-caused augmentations of iNOS mRNA and protein syntheses. in parallel, exposure to LTA increased translocation of nuclear factor-kappa B (NF kappa B) from the cytoplasm to nuclei. Propofol at 50 mu M decreased such translocation. Analyses by an electrophoretic mobility shift and reporter gene further showed that propofol could alleviate LTA-induced transactivation of NF kappa B. Sequentially, propofol decreased phosphorylation of IKK, ERK1/2, MEK1/2, and Raf in LTA-stimulated macrophages. Application of toll-like receptor 2 (TLR2) small interference (si)RNA decreased the translation of this receptor and Raf phosphorylation in LTA-stimulated macrophages. Co-treatment with propofol and TLR2 siRNA synergistically ameliorated LTA-induced iNOS mRNA expression and nitrite production. Thus, this study shows that propofol can downregulate NO biosynthesis via inhibiting iNOS gene expression. The suppressive mechanism occurs possibly through reduction of TLR2-mediated sequential activation of Raf-MEK1/2-ERK1/2-IKK-NF kappa B. (C) 2009 Elsevier Ireland Ltd. All rights reserved.