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首页> 外文期刊>American Journal of Physiology >Glucocorticoid receptor-dependent immunomodulatory effect of ursodeoxycholic acid on liver lymphocytes in mice
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Glucocorticoid receptor-dependent immunomodulatory effect of ursodeoxycholic acid on liver lymphocytes in mice

机译：熊去氧胆酸对小鼠糖皮质激素受体的免疫调节作用

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Although ursodeoxycholic acid (UDCA) has long been used for patients with chronic cholestatic liver diseases, particularly primary biliary cirrhosis, it may modulate the host immune response. This study investigated the effect of UDCA feeding on experimental hepatitis, endotoxin shock, and bacterial infection in mice. C57BL/6 mice were fed a diet supplemented with or without 0.3% (wt/vol) UDCA for 4 wk. UDCA improved hepatocyte injury and survival in concanavalin-A (Con-A)-induced hepatitis by suppressing IFN-gamma production by liver mononu-clear cells (MNC), especially NK and NKT cells. UDCA also increased survival after lipopolysaccharide (LPS)-challenge; however, it increased mortality of mice following Escherichia coli infection due to the worsening of infection. UDCA-fed mice showed suppressed serum IL-18 levels and production of IL-18 from liver Kupffer cells, which together with IL-12 potently induce IFN-gamma production. However, unlike normal mice, exogenous IL-18 pretreatment did not increase the serum IFN-gamma levels after E. coli, LPS, or Con-A challenge in the UDCA-fed mice. Interestingly, however, glucocorticoid receptor (GR) expression was significantly upregulated in the liver MNC of the UDCA-fed mice but not in their whole liver tissue homogenates. Silencing GR in the liver MNC abrogated the suppressive effect of UDCA on LPS- or Con-A-induced IFN-gamma production. Furthermore, RU486, a GR antagonist, restored the serum IFN-gamma level in UDCA-fed mice after E. coli, LPS, or Con-A challenge. Taken together, these results suggest that IFN-gamma-reducing immunomodulatory property of UDCA is mediated by elevated GR in the liver lymphocytes in an IL-12/18-independent manner.
机译：尽管熊去氧胆酸（UDCA）长期用于患有慢性胆汁淤积性肝病，尤其是原发性胆汁性肝硬化的患者，但它可能会调节宿主的免疫反应。这项研究调查了UDCA喂养对小鼠实验性肝炎，内毒素休克和细菌感染的影响。给C57BL / 6小鼠喂食添加或不添加0.3％（wt / vol）UDCA的饮食4周。 UDCA通过抑制肝单核细胞（MNC）特别是NK和NKT细胞产生的IFN-γ来改善伴刀豆球蛋白A（Con-A）诱导的肝炎的肝细胞损伤和存活率。 UDCA还提高了脂多糖（LPS）攻击后的存活率;然而，由于感染的恶化，它增加了大肠杆菌感染后小鼠的死亡率。用UDCA喂养的小鼠显示出抑制的血清IL-18水平和肝库普弗细胞产生的IL-18，与IL-12一起有效诱导IFN-γ的产生。但是，与正常小鼠不同，在以UDCA喂养的小鼠中进行大肠杆菌，LPS或Con-A攻击后，外源IL-18预处理不会增加血清IFN-γ水平。然而，有趣的是，糖皮质激素受体（GR）的表达在UDCA喂养的小鼠的肝脏MNC中显着上调，但在其整个肝组织匀浆中却没有上调。在肝脏中使GR沉默MNC消除了UDCA对LPS或Con-A诱导的IFN-γ产生的抑制作用。此外，在大肠杆菌，LPS或Con-A攻击后，GR拮抗剂RU486恢复了UDCA喂养的小鼠的血清IFN-γ水平。综上所述，这些结果表明UDCA的IFN-γ降低的免疫调节特性是由肝淋巴细胞中IL-12 / 18非依赖性的GR升高所介导的。

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