LIVER X RECEPTOR AGONIST GW3965 DOSE-DEPENDENTLY REGULATES LPS-MEDIATED LIVER INJURY AND MODULATES POSTTRANSCRIPTIONAL TNF- PRODUCTION AND P38 MITOGEN-ACTIVATED PROTEIN KINASE ACTIVATION IN LIVER MACROPHAGES
LIVER X RECEPTOR AGONIST GW3965 DOSE-DEPENDENTLY REGULATES LPS-MEDIATED LIVER INJURY AND MODULATES POSTTRANSCRIPTIONAL TNF- PRODUCTION AND P38 MITOGEN-ACTIVATED PROTEIN KINASE ACTIVATION IN LIVER MACROPHAGES
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DOI：
10.1097/shk.0b013e3181a47f85
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发表时间：
2009-11
期刊：
影响因子：
3.1
通讯作者：
Y. Wang;M. Dahle;K. Steffensen;F. Reinholt;J. Collins;C. Thiemermann;A. Aasen;J. Gustafsson;Jacob E. Wang
中科院分区：
文献类型：
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作者：
Y. Wang;M. Dahle;K. Steffensen;F. Reinholt;J. Collins;C. Thiemermann;A. Aasen;J. Gustafsson;Jacob E. Wang
调节宿主对感染的炎症反应可能是改善脓毒症和器官损伤患者预后的关键途径。我们以前报道，预处理大鼠与肝脏X受体（LXR）激动剂GW 3965减少与内毒素血症相关的肝损伤，并减弱大鼠枯否细胞产生的TNF-α。在这里，我们研究了GW 3965对内毒素血症大鼠模型中肝损伤和细胞因子产生的剂量依赖性作用，并探讨了枯否细胞中TNF-α衰减的机制。在输注LPS和肽聚糖前30分钟给予低剂量GW 3965（0.1或0.3 mg/kg）显著减弱了肝损伤标志物丙氨酸氨基转移酶和胆红素（6 h）以及与内毒素血症相关的炎症介质TNF-α（1 h）和前列腺素E2（6 h）的血浆水平升高。相反，用更高剂量的GW 3965（1.0mg/kg）预处理没有这种效果。在大鼠枯否细胞原代培养物中的研究表明，LXR激动剂处理减弱了TNF-α的分泌和细胞相关水平，而TNF-α mRNA水平没有改变。磷酸化的p38丝裂原活化蛋白激酶，它在转录后水平上的TNF-α的产生中起着重要作用，在枯否细胞中被GW 3965处理减弱。在小鼠LXR缺陷型Kupffer细胞中的实验表明，与LXR--/-和野生型Kupffer细胞相比，当用LPS攻击时，LXR--/-小鼠的Kupffer细胞中TNF-α的产生增强。总之，这些结果支持LXR介导的肝损伤衰减的新机制，通过干扰枯否细胞中TNF-α的转录后调节。
Modulation of the host inflammatory response to infection may be a key approach to improve the outcome of patients with sepsis and organ injury. We previously reported that pretreatment of rats with the liver X receptor (LXR) agonist GW3965 reduced the liver injury associated with endotoxemia and attenuated the production of TNF- by rat Kupffer cells. Here, we examine the dose-dependent effect of GW3965 on liver injury and cytokine production in a rat model of endotoxemia and explore the mechanisms underlying TNF- attenuation in Kupffer cells. Low doses of GW3965 (0.1 or 0.3 mg/kg) administered 30 min before infusion of LPS and peptidoglycan significantly attenuated the increase in plasma levels of the liver injury markers alanine aminotransferase and bilirubin (6 h) as well as the inflammatory mediators TNF- (1 h) and prostaglandin E2 (6 h) associated with endotoxemia. In contrast, pretreatment with a higher dose of GW3965 (1.0 mg/kg) had no such effect. Studies in primary cultures of rat Kupffer cells demonstrated that LXR agonist treatment attenuated both the secreted and cell-associated levels of TNF-, whereas TNF- mRNA levels were not altered. Phosphorylated p38 mitogen-activated protein kinase, which plays a major role in production of TNF- at the posttranscriptional level, was attenuated by GW3965 treatment in Kupffer cells. Experiments in murine LXR-deficient Kupffer cells demonstrated enhanced production of TNF- in Kupffer cells from LXR--/- mice when challenged with LPS compared with LXR--/- and wild-type Kupffer cells. Taken together, these results argue in favor of a novel mechanism for LXR-mediated attenuation of liver injury by interfering with posttranscriptional regulation of TNF- in Kupffer cells.