Hepatitis C virus core protein activates ERK and p38 MAPK in cooperation with ethanol in transgenic mice
Hepatitis C virus core protein activates ERK and p38 MAPK in cooperation with ethanol in transgenic mice
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DOI：
10.1002/hep.1840380408
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发表时间：
2003-10
期刊：
影响因子：
13.5
通讯作者：
T. Tsutsumi;Tetsuro Suzuki;K. Moriya;Y. Shintani;H. Fujie;H. Miyoshi;Y. Matsuura;K. Koike;T. Miyamura
中科院分区：
文献类型：
--
作者：
T. Tsutsumi;Tetsuro Suzuki;K. Moriya;Y. Shintani;H. Fujie;H. Miyoshi;Y. Matsuura;K. Koike;T. Miyamura
在人类慢性丙型肝炎中，酒精摄入是加速肝癌发生的协同因素。最近，我们发现饲喂含乙醇饲料的丙型肝炎病毒(丙型肝炎病毒)核心转基因小鼠体内的活性氧(ROS)显著增加。由于先前的研究表明ROS与丝裂原活化蛋白激酶(MAPK)密切相关，我们检测了短期酒精喂养的核心转基因和非转基因小鼠肝脏中c-jun氨基末端激酶、p38MAPK和细胞外信号调节激酶(ERK)的活性。与非转基因小鼠相比，核心转基因小鼠的ERK和p38MAPK活性增加，而正常饮食的核心转基因小鼠ERK和p38MAPK活性均未被激活。此外，p38MAPK和ERK下游通路--环磷酸腺苷和血清反应元件的活性也增加。通过基因芯片和实时定量聚合酶链式反应对基因表达谱的比较发现，在酒精喂养的核心转基因小鼠中，与细胞转化相关的Galectin-1显著增加。另一方面，对保护细胞免受氧化应激起关键作用的谷胱甘肽S转移酶(GST)减少。综上所述，这些结果表明，丙型肝炎病毒核心蛋白与乙醇协同激活一些MAPK通路，并导致多个基因的调控，在高酒精摄入的丙型肝炎感染患者的肝病发病机制中起重要作用。(《肝病》2003；38：820-828)。
In human chronic hepatitis C, alcohol intake is a synergistic factor for the acceleration of hepatocarcinogenesis. Recently, we showed a significant increase of reactive oxygen species (ROS) in hepatitis C virus (HCV) core‐transgenic mice fed ethanol‐containing diets. Because previous studies indicated that ROS is closely associated with mitogen‐activated protein kinases (MAPK), we examined activities of c‐Jun N‐terminal kinase, p38 MAPK, and extracellular signal‐regulated kinase (ERK) in the liver of core‐transgenic and nontransgenic mice with short‐term ethanol feeding. Activity of ERK and p38 MAPK was increased in core‐transgenic mice compared with nontransgenic mice, whereas neither ERK nor p38 MAPK was activated in core‐transgenic mice with normal diets. In addition, activity of cyclic‐AMP and serum responsive element, downstream pathways of p38 MAPK and ERK, was also increased. Comparison of gene expression profiles by cDNA microarray and real‐time PCR revealed that galectin‐1, which is associated with cell transformation, was significantly increased in ethanol‐fed core‐transgenic mice. On the other hand, glutathione S‐transferase (GST), which plays a key role in protecting cells from oxidative stress, was decreased. In conclusion, these results suggest that HCV core protein cooperates with ethanol for the activation of some MAPK pathways, and leads to the modulation of several genes, contributing to the pathogenesis of liver disease of HCV‐ infected patients with high ethanol consumption. (Hepatology 2003;38:820–828).