Ketamine reduces LPS-induced HMGB1 via activation of the Nrf2/HO-1 pathway and NF-κB suppression
Ketamine reduces LPS-induced HMGB1 via activation of the Nrf2/HO-1 pathway and NF-κB suppression
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DOI：
10.1097/ta.0000000000000588
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发表时间：
2015-04-01
影响因子：
3.4
通讯作者：
Zhao, Baisong
中科院分区：
文献类型：
--
作者：
Tan, Yonghong;Wang, Qiong;Zhao, Baisong
背景：氯胺酮作为一种麻醉剂，具有抗炎作用。在本研究中，我们调查氯胺酮是否抑制释放高迁移率族蛋白1（HMGB 1），脓毒症的晚期细胞因子，在脂多糖（LPS）刺激的巨噬细胞通过血红素加氧酶-1（HO-1）induction.METHODS：巨噬细胞与不同浓度的氯胺酮预孵育，然后用LPS（1 μ g/mL）处理。收集细胞培养上清液，通过酶联免疫吸附试验测定炎症介质（HMGB 1、一氧化氮、肿瘤坏死因子-α和白细胞介素1 β）。Western blot检测HO-1蛋白表达、I κ B-α的磷酸化和降解、核因子E2相关因子2和核因子κ B（NF-κ B）p65的核转位。此外，为了进一步确定HO-1在这一过程中的作用，锡原卟啉（SnPP），HO-1抑制剂，used.RESULTS：氯胺酮治疗剂量依赖性衰减的水平增加的促炎介质（HMGB 1，一氧化氮，肿瘤坏死因子α，白细胞介素1A）和增加HO-1蛋白在LPS激活的巨噬细胞的表达。此外，氯胺酮抑制巨噬细胞中I κ B-α的磷酸化和降解以及LPS刺激的NF-κ B p65的核转位。此外，本研究还证实氯胺酮通过核因子E2 Y相关因子2的核转位诱导巨噬细胞HO-1的表达。结论：氯胺酮可抑制LPS刺激的巨噬细胞释放HMGB 1，其抑制作用可能与激活Nrf 2/HO-1通路和抑制NF-κ B B有关。版权所有（C）2015威科医疗集团All rights reserved.
BACKGROUND: Ketamine, as an anesthetic agent, has an anti-inflammatory effect. In the present study, we investigated whether ketamine inhibits release of high mobility group box 1 (HMGB1), a late-phase cytokine of sepsis, in lipopolysaccharide (LPS)-stimulated macrophages through heme oxygenase-1 (HO-1) induction.METHODS: Macrophages were preincubated with various concentrations of ketamine and then treated with LPS (1 mu g/mL). The cell culture supernatants were collected to measure inflammatory mediators (HMGB1, nitric oxide, tumor necrosis factor-alpha, and interleukin 1 beta) by enzyme-linked immunosorbent assay. Moreover, HO-1 protein expression, the phosphorylation and degradation of I kappa B-alpha, and the nuclear translocation of nuclear factor E2-related factor 2 and nuclear factor kappa B (NF-kappa B) p65 were tested by Western blot analysis. In addition, to further identify the role of HO-1 in this process, tin protoporphyrin (SnPP), an HO-1 inhibitor, was used.RESULTS: Ketamine treatment dose-dependently attenuated the increased levels of proinflammatory mediators (HMGB1, nitric oxide, tumor necrosis factor alpha, and interleukin 1A) and increased the HO-1 protein expression in LPS-activated macrophages. Furthermore, ketamine suppressed the phosphorylation and degradation of I kappa B-alpha as well as the LPS-stimulated nuclear translocation of NF-kappa B p65 in macrophages. In addition, the present study also demonstrated that ketamine induced HO-1 expression through the nuclear translocation of nuclear factor E2Yrelated factor 2 in macrophages. The effects of ketamine on LPS-induced proinflammatory cytokines production were partially reversed by the HO inhibitor tin protoporphyrin (SnPP).CONCLUSION: Ketamine inhibits the release of HMGB1 in LPS-stimulated macrophages, and this effect is at least partly mediated by the activation of the Nrf2/HO-1 pathway and NF-kappa B suppression. Copyright (C) 2015 Wolters Kluwer Health, Inc. All rights reserved.