Inhibitory effect of naringin on lipopolysaccharide (LPS)-induced endotoxin shock in mice and nitric oxide production in RAW 264.7 macrophages
Inhibitory effect of naringin on lipopolysaccharide (LPS)-induced endotoxin shock in mice and nitric oxide production in RAW 264.7 macrophages
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DOI：
10.1016/j.lfs.2005.04.051
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发表时间：
2006-01-11
期刊：
影响因子：
6.1
通讯作者：
Ishikawa, M
中科院分区：
文献类型：
--
作者：
Kanno, S;Shouji, A;Ishikawa, M
已知脂多糖（LPS）通过产生炎症调节剂如肿瘤坏死因子α（TNF-α）或一氧化氮（NO）诱导内毒素休克。在这项研究中，我们研究了黄酮类化合物之一的柚皮苷（NG）对LPS诱导的小鼠内毒素休克和RAW 264.7巨噬细胞产生NO的影响。对于腹膜内（i. p.，20 mg/kg）注射LPS后48 h，单独给予LPS（n = 10）或预先给予NG 10、30和60 mg/kg（i. p.）组（n = 10）分别为0%或10%、50%和70%。NG剂量依赖性地抑制LPS诱导的TNF-α的产生。通过亚硝酸盐形成测定，LPS诱导的6小时NO生成量（125.89 +/- 16.35 μ M）分别被30或60 mg/kg NG显著降低为49.49 +/- 4.81或27.91 +/- 1.81 μ M（与单独的LPS相比，P < 0.01）。为了进一步研究NG抑制LPS诱导的内毒素休克的机制，我们使用了体外模型RAW 264.7小鼠巨噬细胞。NG（1 mM）抑制LPS（0.01、0.1或1 μ g/ml）诱导的NO产生和炎性基因产物如诱导型NO合酶（iNOS）、TNF-α、诱导型环氧合酶（考克斯-2）和白细胞介素-6（IL-6）的表达，如通过RT-PCR测定所确定的。电泳迁移率变动分析和报告基因分析发现NG能阻断LPS诱导的NF-κ B的转录活性。这些发现表明，抑制LPS诱导的死亡率和NO的生产由NG是由于抑制NF-κ B的活化。(c)2005年爱思唯尔公司All rights reserved.
Lipopolysaccharide (LPS) has been known to induce endotoxin shock via production of inflammatory modulators such as tumor necrosis factor alpha (TNF-alpha), or nitric oxide (NO). In this study, we have examined the effect of naringin (NG), one of the flavonoids, on LPS-induced endotoxin shock in mice and NO production in RAW 264.7 macrophages. For intraperitoneal (i.p., 20 mg/kg) injection of LPS at 48 h, the survival rate of mice administered with LPS alone (n = 10) or pretreated with NG at 10, 30 and 60 mg/kg (i.p.) group (n = 10) was 0% or 10%, 50% and 70%, respectively. NG dose-dependently suppressed LPS-induced production of TNF-a. LPS-induced production of NO at 6 h (125.89 +/- 16.35 mu M), as measured by nitrite formation, was significantly reduced by NG at 30 or 60 mg/kg for 49.49 +/- 4.81 or 27.91 +/- 1.81 mu M (P < 0.01 vs. LPS alone), respectively. To further examine the mechanism by which NG suppresses LPS-induced endotoxin shock, we used an in vitro model, RAW 264.7 mouse macrophage cells. NG (I mM) suppressed LPS (0.01, 0.1 or 1 mu g/ml)-induced production of NO and the expression of inflammatory gene products such as inducible NO synthase (iNOS), TNF-a, inducible cyclooxygenase (COX-2) and interleukin-6 (IL-6) as determined by RT-PCR assay. NG was found to have blocked the LPS-induced transcriptional activity of NF-KB in electrophoretic mobility shift assay and reporter assay. These findings suggest that suppression of the LPS-induced mortality and production of NO by NG is due to inhibition of the activation of NF-KB. (c) 2005 Elsevier Inc. All rights reserved.