Regulatory Effect of JAK2/STAT3 on the Immune Function of Endotoxin-tolerant Dendritic Cells and its Involvement in Acute Liver Failure  

作　　者：Yukai Chen Chaochen Hou Naibin Yang Yanyan Yang Youran Chen Deyong Kong Yuchun Jiang Minghao Lin Sijie Zheng Shanshan Li Mingqin Lu 

机构地区：[1]Ningbo Puji Hospital,Ningbo,Zhejiang,China [2]Department of Infectious Diseases,The First Affiliated Hospital of Wenzhou Medical University,Wenzhou,Zhejiang,China [3]Department of Infectious Diseases,Ningbo First Hospital,Ningbo,Zhejiang,China

出　　处：《Journal of Clinical and Translational Hepatology》2022年第5期879-890,共12页临床与转化肝病杂志（英文版）

基　　金：supported by Zhejiang Provincial Natural Science Foundation of China under Grant No.LY18H030010.

摘　　要：Background and Aims:Acute liver failure(ALF)is a potentially fatal clinical syndrome with no effective treatment.This study aimed to explore the role of Janus kinase 2/signal transducer and activator of transcription 3(JAK2/STAT3)pathway in modulating the phenotype and immune function of endotoxin-tolerant dendritic cells(ETDCs).In addition,we explored the use of EDTCs in an experimental model of ALF and investigated the associated mechanisms.Methods:In the in vitro experiment,ETDCs were transfected with adenovirus to induce SOCS1^(+/+)ETDCs and SOCS1^(−/−)ETDCs.Thereafter,costimulatory molecules and mixed lymphocyte reaction were assessed.Experimental mice were randomly divided into normal control,ALF,ALF+mock-ETDCs,ALF+SOCS1^(+/+)ETDCs,ALF+AG490,and ALF+AG490+SOCS1^(+/+)ETDCs groups.We examined the therapeutic effect of adoptive cellular immunotherapy by tail-vein injection of target ETDCs 12 h before ALF modeling.AG490,a JAK2/STAT3 inhibitor,was used in the in vivo experiment to further explore the protective mechanism of SOCS1^(+/+)ETDCs.Results:Compared with control ETDCs,SOCS1^(+/+)ETDCs had lower expression of costimulatory molecules,weaker allostimulatory ability,lower levels of IL-6 and TNF-αexpression and higher IL-10 secretion.SOCS1^(−/−)ETDCs showed the opposite results.In the in vivo experiments,the ALF+SOCS1^(+/+)ETDCs and ALF+AG490+SOCS1^(+/+)ETDCs groups showed less pathological damage and suppressed activation of JAK2/STAT3 pathway.The changes were more pronounced in the ALF+AG490+SOCS1^(+/+)ETDCs group.Infusion of SOCS1^(+/+)ETDCs had a protective effect against ALF possibly via inhibition of JAK2 and STAT3 phosphorylation.Conclusions:The SOCS1 gene had an important role in induction of endotoxin tolerance.SOCS1^(+/+)ETDCs alleviated lipopolysaccharide/D-galactosamine-induced ALF by downregulating the JAK2/STAT3 signaling pathway.

关 键 词：Liver failure Acute Janus kinase 2/signal transducers and activators of transcription 3(JAK2/STAT3) Endotoxin tolerance Dendritic cells 

分 类 号：R575.3[医药卫生—消化系统]