Endogenous interleukin-4 regulates glutathione synthesis following acetaminophen-induced liver injury in mice.
Endogenous interleukin-4 regulates glutathione synthesis following acetaminophen-induced liver injury in mice.
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DOI：
10.1021/tx2003992
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发表时间：
2012-01-13
影响因子：
4.1
通讯作者：
Pohl LR
中科院分区：
文献类型：
--
作者：
Ryan PM;Bourdi M;Korrapati MC;Proctor WR;Vasquez RA;Yee SB;Quinn TD;Chakraborty M;Pohl LR
在最近的一项研究中，我们报道了白介素4对对乙酰氨基酚(APAP)诱导的肝损伤(AILI)具有保护作用，但其保护机制尚不清楚。在这里，我们进行了更详细的研究，并表明IL-4可能通过调节谷胱甘肽(GSH)的合成来控制AILI的严重程度。在本研究中，IL-4在AILI中的保护作用是通过显示IL-4基因缺陷(IL-4−/−)或抗体缺失的C57BL/6J小鼠比未缺失IL-4的小鼠更容易受到AILI的影响。IL-4−/−小鼠易感性的增加不是由于肝脏APAP蛋白加合物水平的升高，而是与肝脏谷胱甘肽的持续降低有关，这归因于γ-谷氨酰半胱氨酸连接酶(γ-GCL)基因表达的降低。此外，在醋氨酚治疗后给IL-4−/−小鼠注射重组IL-4可减轻肝损伤的严重程度，并增加γ-GCL和谷胱甘肽水平。我们还报道，在经APAP治疗的IL-4−/−小鼠中，谷胱甘肽的持续降低似乎通过导致c-jun-N末端激酶的持续激活而导致肝损伤的加重，因为在经APAP治疗后的24小时内，IL-4−/−小鼠体内磷酸化的JNK的水平仍然显著升高。这些结果首次表明，在细胞应激条件下，IL-4对肝脏中谷胱甘肽的合成具有调节作用。这一机制似乎至少部分归因于IL-4对小鼠AILI的保护作用，并且可能不仅在人类AILI中具有类似的作用，而且在其他药物和病因引起的肝脏病理中也具有类似的作用。
In a recent study, we reported that interleukin (IL)-4 had a protective role against acetaminophen (APAP)-induced liver injury (AILI), although the mechanism of protection was unclear. Here, we carried out more detailed investigations and have shown that one way IL-4 may control the severity of AILI is by regulating glutathione (GSH) synthesis. In the present studies, the protective role of IL-4 in AILI was established definitively by showing that C57BL/6J mice made deficient in IL-4 genetically (IL-4−/−) or by depletion with an antibody, were more susceptible to AILI than mice not depleted of IL-4. The increased susceptibility of IL-4−/− mice was not due to elevated levels of hepatic APAP-protein adducts, but was associated with a prolonged reduction in hepatic GSH that was attributed to decreased gene expression of γ-glutamylcysteine ligase (γ-GCL). Moreover, administration of recombinant IL-4 to IL-4−/− mice post-acetaminophen treatment diminished the severity of liver injury and increased γ-GCL and GSH levels. We also report that the prolonged reduction of GSH in APAP-treated IL-4−/− mice appeared to contribute towards increased liver injury by causing a sustained activation of c-Jun-N-terminal kinase (JNK), since levels of phosphorylated JNK remained significantly higher in the IL-4−/− mice up to 24 hours after APAP treatment Overall these results show for the first time that IL-4 has a role in regulating the synthesis of GSH in the liver under conditions of cellular stress. This mechanism appears to be responsible at least in part for the protective role of IL-4 against AILI in mice and may have a similar role not only in AILI in humans, but also in pathologies of the liver caused by other drugs and etiologies.
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影响因子：
7
作者：
Dröge, W;Breitkreutz, R
通讯作者：
Breitkreutz, R
影响因子：
4.8
作者：
Akai, Sho;Hosomi, Hiroko;Yokoi, Tsuyoshi
通讯作者：
Yokoi, Tsuyoshi
影响因子：
4.1
作者：
Bourdi, Mohammed;Eiras, Daniel P.;Pohl, Lance R.
通讯作者：
Pohl, Lance R.
影响因子：
13.5
作者：
Bourdi, M;Masubuchi, Y;Pohl, LR
通讯作者：
Pohl, LR
DOI：
10.1126/science.1168988
发表时间：
2009-03-27
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Chen GY;Tang J;Zheng P;Liu Y
通讯作者：
Liu Y