MAPK signaling contributes to rotaviral-induced cholangiocyte injury and viral replication
MAPK signaling contributes to rotaviral-induced cholangiocyte injury and viral replication
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DOI：
10.1016/j.surg.2007.03.008
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发表时间：
2007-08-01
期刊：
影响因子：
3.8
通讯作者：
Tiao, Greg
中科院分区：
文献类型：
--
作者：
Jafri, Mubeen;Donnelly, Bryan;Tiao, Greg
背景。胆道闭锁是一种新生儿疾病，导致胆道阻塞。恒河轮状病毒（RRV）感染小鼠可导致一种类似人类疾病的胆管病。有丝分裂原相关蛋白激酶（MAPK）信号通路可以通过病毒与细胞表面受体的结合而激活。我们假设PLRV感染胆管细胞导致MAPK信号的激活。使用Western blots对PLRV感染或对照的BALB/c幼崽或永生化胆管进行肝外胆管分析，检测MAPK家族磷酸化成员：p38、ERK 1/2、JNK 1/2和下游转录因子。使用MAPK抑制剂下调其活性。抑制mapk后，评估胆管细胞的病毒复制和细胞溶解。所有MAPK的磷酸化在rrv感染小鼠和胆管细胞中升高。几种下游转录因子的体外活性增加。抑制p38和ERK 1/2导致病毒复制减少。erk112抑制降低细胞溶解，但不影响病毒进入或结合。RRV感染胆管细胞导致MAPK信号的增加。抑制p38和erk1 /2影响轮状病毒的复制能力。这些新发现为深入了解plrv诱导的胆管细胞损伤的信号级联提供了线索。
Background. Biliary atresia is a disease of newborns that results in obliteration of the biliary tree. Infection of mice with rhesus rotavirus (RRV) results in a cholangiopathy mirroring human disease. The Mitogen Associated Protein Kinase (MAPK) signaling pathway can be activated by viral binding to cell-surface receptors. We hypothesized that PLRV infection of cholangiocytes results in activation of MAPK signaling.Methods. Extrahepatic bile ducts from BALB/c pups or immortalized cholangiocyles subjected to PLRV infection or control were analyzed, using Western blots, for phosphorylated members of the MAPK family: p38, ERK 1/2, JNK 1/2, and downstream, transcription factors. Inhibitors of the MAPK were used to downregulate activity. Viral replication and cytolysis in cholangiocytes were evaluated post-MAPK inhibition.Results. Phosphorylation of all MAPK increased in RRV-infected mice and cholangiocytes. Several downstream transcription factors had increased activity in vitro. Inhibition of p38 and ERK 1/2 resulted in decreased viral replication. ERK 112 inhibition decreased cytolysis without affecting viral entry or binding.Conclusions. RRV infection of cholangiocytes resulted in increased MAPK signaling. Inhibition of p38 and ERK 1/2 influenced the ability of rotavirus to replicate. These novel findings provide insight into the signaling cascade involved in PLRV-induced cholangiocyte injury.