Remifentanil upregulates hepatic IL-18 binding protein (IL-18BP) expression through transcriptional control
Remifentanil upregulates hepatic IL-18 binding protein (IL-18BP) expression through transcriptional control
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DOI：
10.1038/s41374-018-0111-y
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发表时间：
2018-12-01
影响因子：
5
通讯作者：
Tian, Jie
中科院分区：
文献类型：
--
作者：
Liu, Xiaohua;Yang, Hao;Tian, Jie
Interleukin (IL)-18 plays an important role in liver ischemia/reperfusion (I/R) injury. We have previously demonstrated that remifentanil protects against liver I/R injury by upregulating the hepatic expression of IL-18-binding protein (IL-18BP), a natural IL-18 inhibitor. The current study was performed to further clarify the effects of remifentanil on IL-18BP expression in the liver as well as investigate the underlying mechanisms. In Sprague-Dawley (SD) rats, we demonstrated that remifentanil significantly increased the expression of IL-18BP in normal rat liver tissue over a 24-h time period with maximal expression at 24 h after treatment. The upregulation of remifentanil on IL-18BP expression displayed similar trends in in vitro cellular studies, including mouse primary hepatocytes, normal human hepatocyte LO2, and mouse hepatoma cells Hep1-6. In LO2 cells, preexposure of the cells to remifentanil significantly inhibited IL-18-activated p65 NF-kappa B phosphorylation, and the inhibition was absent when the cells were transfected with IL-18BP siRNA, indicating the functional effects of IL-18BP induced by remifentanil. Pretreatment with actinomycin D abolished remifentanil-induced upregulation of IL-18BP mRNA, suggesting that the induction occurred at the transcriptional level. This was further supported by the luciferase reporter assay, which demonstrated that remifentanil treatment significantly increased transcription of the IL-18BP promoter. Both western blot analysis and ChIP assays showed that STAT1 and C/EBP beta were activated by remifentanil. Furthermore, remifentanil failed to upregulate IL-18BP expression after silencing STAT1 or C/EBP beta gene expression. These findings demonstrate that remifentanil could upregulate hepatic IL-18BP expression through transcriptional activation of the IL-18BP promoter, and STAT1 and C/EBP beta are two key transcriptional factors involved in this process.
