期刊
TOXICOLOGICAL SCIENCES
卷 170, 期 2, 页码 499-508出版社
OXFORD UNIV PRESS
DOI: 10.1093/toxsci/kfz112
关键词
exosomes; idiosyncratic drug-induced liver injury; immune response; hepatocytes; monocytes
类别
资金
- National Center for Advancing Translational Sciences (NCATS), National Institutes of Health [5UL1TR001111]
- Eshelman Institute for Innovation Award
- National Institutes of Health, National Institute of Environmental Health Sciences (NIEHS) Toxicology Training Grant [T32-ES007126]
- Janssen Research and Development, LLC
Most idiosyncratic drug-induced liver injury appears to result from an adaptive immune attack on the liver. Recent evidence suggests that the T-cell response may be facilitated by the loss of immune tolerance. In this study, we explored the hypothesis that constitutively released hepatocyte-derived exosomes (HDE) are important for maintaining normal liver immune tolerance. Exosomes were isolated from the conditioned medium of primary human hepatocytes via polymer precipitation. Mock controls were prepared by processing fresh medium that was not hepatocyte exposed with precipitation reagent. THP-1 monocytes were then treated with HDE or an equivalent volume of mock control for 24 h, followed by a 6-h stimulation with LPS. HDE exposure resulted in a significant decrease in the LPS-induced media levels of interleukin-1 beta and interleukin-8. Gene expression profiling performed in THP-1 cells just prior to LPS-induced stimulation identified a significant decrease among genes associated with innate immune response. MicroRNA (miRNA) profiling was performed on the HDE to identify exosome contents that may drive immune suppression. Many of the predicted mRNA target genes for the most abundant microRNAs in HDE were among the differentially expressed genes in THP-1 cells. Taken together, our data suggest that HDE play a role in maintaining normal liver immune tolerance. Future experiments will explore the possibility that drugs causing idiosyncratic liver injury promote the loss of homeostatic HDE signaling.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据