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 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.

RESULTS

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.

CONCLUSIONS

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.