Publikationsdatum:
2016-09-18
Beschreibung:
The central purpose of this study was to investigate therapeutic effects of the botanical derivative kinsenoside (KD) in experimental autoimmune hepatitis (AIH). Treatment with KD substantially reduced hepatic histopathological damage, induced by lymphocyte infiltration and pro-inflammatory cytokines, in ConA-induced T cell-mediated hepatitis, and in dendritic cells loaded with hepatocellular carcinoma cells (DC/Hepa1-6) induced murine AIH. Interactions between immune cells after KD treatment in AIH were detected by anti-CD8 antibody blocking, CD8 + T cells sorting, and vaccinated mice with KD-pretreated DCs in a DC/Hepa1-6 model. Our results showed that KD inhibited the elevated expressions of CD86 and MHC-II, densities of chemokine receptor CCR7, and extensive migration to lymph nodes, and increased the PD-L1 level of DCs, followed by suppressing CD8 + T cells characterized as low differentiation and cytotoxicity, and eliciting cytokines balance. Furthermore, biochemical analysis, 2D fingerprint screen and 3D molecular docking results showed that KD bound to the VEGFR2 kinase domain, which inhibiting the metabolism-related PI3K-AKT pathway in DCs and DC-modulated CD8 + T cells to lower the mitochondrial membrane potential (MMP) and glucose/lipid utilization ratio in both cells. KD reversed the activation of the PI3K-AKT pathway by 740 Y-P (PI3K agonist), thereby impeding the translocation and dimerization of STAT3 and synergistically blocking the inflammation-related JAK2-STAT3 pathway in DCs and DC-modulated T cells. Conclusion : KD treatment elicits immunosuppression against autoimmune liver injury by targeting VEGFR2, followed by diminishing the cross-talk of metabolism-related PI3K-AKT and inflammation-related JAK2-STAT3 pathways, thereby disrupts DC-induced cross-priming of CD8 + T cell responses. This article is protected by copyright. All rights reserved.
Print ISSN:
0270-9139
Digitale ISSN:
1527-3350
Thema:
Medizin
Permalink