Chen Yukai, Hou Chaochen, Yang Naibin, Yang Yanyan, Chen Youran, Kong Deyong, Jiang Yuchun, Lin Minghao, Zheng Sijie, Li Shanshan, Lu Mingqin
Ningbo Puji Hospital, Ningbo, Zhejiang, China.
Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
J Clin Transl Hepatol. 2022 Oct 28;10(5):879-890. doi: 10.14218/JCTH.2021.00175. Epub 2022 Jan 4.
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.
In the experiment, ETDCs were transfected with adenovirus to induce SOCS1ETDCs and SOCS1ETDCs. Thereafter, costimulatory molecules and mixed lymphocyte reaction were assessed. Experimental mice were randomly divided into normal control, ALF, ALF+mock-ETDCs, ALF+SOCS1ETDCs, ALF+AG490, and ALF+AG490+SOCS1ETDCs 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 experiment to further explore the protective mechanism of SOCS1ETDCs.
Compared with control ETDCs, SOCS1ETDCs had lower expression of costimulatory molecules, weaker allostimulatory ability, lower levels of IL-6 and TNF-α expression and higher IL-10 secretion. SOCS1ETDCs showed the opposite results. In the experiments, the ALF+SOCS1ETDCs and ALF+AG490+SOCS1ETDCs groups showed less pathological damage and suppressed activation of JAK2/STAT3 pathway. The changes were more pronounced in the ALF+AG490+SOCS1ETDCs group. Infusion of SOCS1ETDCs had a protective effect against ALF possibly via inhibition of JAK2 and STAT3 phosphorylation.
The gene had an important role in induction of endotoxin tolerance. SOCS1ETDCs alleviated lipopolysaccharide/D-galactosamine-induced ALF by downregulating the JAK2/STAT3 signaling pathway.
急性肝衰竭（ALF）是一种潜在致命的临床综合征，目前尚无有效治疗方法。本研究旨在探讨Janus激酶2/信号转导与转录激活因子3（JAK2/STAT3）通路在调节内毒素耐受树突状细胞（ETDCs）表型和免疫功能中的作用。此外，我们还在ALF实验模型中探索了ETDCs的应用并研究了相关机制。
在实验中，用腺病毒转染ETDCs以诱导SOCS1ETDCs和SOCS1ETDCs。此后，评估共刺激分子和混合淋巴细胞反应。将实验小鼠随机分为正常对照、ALF、ALF+模拟ETDCs、ALF+SOCS1ETDCs、ALF+AG490以及ALF+AG490+SOCS1ETDCs组。在ALF建模前12小时通过尾静脉注射靶ETDCs来检测过继性细胞免疫治疗的疗效。实验中使用JAK2/STAT3抑制剂AG490进一步探究SOCS1ETDCs的保护机制。
与对照ETDCs相比，SOCS1ETDCs的共刺激分子表达较低，同种异体刺激能力较弱，IL-6和TNF-α表达水平较低，而IL-10分泌较高。SOCS1ETDCs表现出相反的结果。在实验中，ALF+SOCS1ETDCs组和ALF+AG490+SOCS1ETDCs组显示出较少的病理损伤且JAK2/STAT3通路的激活受到抑制。在ALF+AG490+SOCS1ETDCs组中这些变化更为明显。输注SOCS1ETDCs可能通过抑制JAK2和STAT3磷酸化对ALF具有保护作用。
该基因在诱导内毒素耐受中起重要作用。SOCS1ETDCs通过下调JAK2/STAT3信号通路减轻脂多糖/D-半乳糖胺诱导的ALF。
