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

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-α expression 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.