Effects of kinsenoside, a potential immunosuppressive drug for autoimmune hepatitis, on dendritic cells/CD8+T cells communication in mice

Abstract

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 proinflammatory cytokines, in concanavalin A-induced T-cell-mediated hepatitis, and in dendritic cells (DCs) 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 1 T cell sorting, and vaccinated mice with KD-pretreated DCs in a DC/Hepa1-6 model. These results showed that KD inhibited the elevated expressions of CD86 and major histocompatibility complex II, densities of chemokine receptor C-C chemokine receptor type 7, and extensive migration to lymph nodes, and increased the programmed death ligand 1 level of DCs, followed by suppressing CD8 1 T cells, characterized as low differentiation and cytotoxicity, and eliciting cytokines balance. Furthermore, biochemical analysis, two-dimensional fingerprint screen and three-dimensional molecular docking results showed that KD bound to the vascular endothelial growth factor receptor 2 (VEGFR2) kinase domain, which inhibited the metabolism-related phosphatidylinositol 3 kinase/protein kinase B (PI3K-AKT) pathway in DCs and DC-modulated CD81 T cells to lower the mitochondrial membrane potential and glucose/lipid utilization ratio in both cells. KD reversed activation of the PI3K-AKT pathway by 740 Y-P (PI3K agonist), thereby impeding the translocation and dimerization of signal transducer and activators of transcription (STAT) 3 and synergistically blocking the inflammation-related Janus kinase (JAK) 2/STAT3 pathway in DCs and DCmodulated 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, and thereby disrupts DC-induced cross-priming of CD8 1 T cell responses. (HEPATOLOGY 2016;64:2135-2150).

Immune and Metabolic Regulation Mechanism of Dangguiliuhuang Decoction against Insulin Resistance and Hepatic Steatosis

“…Cell suspensions were prepared from spleen, lymph nodes, VAT, or liver of ob/ob mice as previously described (Chang et al, 2015; Xiang et al, 2016). DC single-cell suspensions were obtained from bone marrow following standard procedures.…”

“…Quantitative real-time PCR (qRT-PCR) was performed as described previously (Xiang et al, 2016). In brief, total RNA was isolated from cells, liver, or VAT using TRizol reagent, and reverse transcribed with the Revert Aid First strand cDNA synthesis kit (Invitrogen, USA) with random primers based on the manufacturer's instructions.…”

Optimization of Ultrasound Assisted Extraction (UAE) of Kinsenoside Compound from Anoectochilus roxburghii (Wall.) Lindl by Response Surface Methodology (RSM)

“…Researchers have found that kinsenoside had a different multiple pharmacologic activity compared with polysaccharide and flavonoids [5][6][7][8]. As a potential immunosuppressive drug for autoimmune hepatitis, it has a vascular protective effect under high glucose conditions and has been found to enhance the oxidative resistance of diabetic mice [9][10][11]. In addition, it has a reparative effect on damaged insulin cells and some other functions, such as anti-hyperliposis, anti-hyperglycemia, anti-osteoporosis, etc.…”

Ginsenoside Rh2 reverses cyclophosphamide-induced immune deficiency by regulating fatty acid metabolism

“…When there is sufficient sterol, SREBP‐1 stays in the endoplasmic reticulum; however, when sterol is insufficient, SREBP‐1 is translocated to the Golgi, where it is cleaved and enters the nucleus to participate in the transcription of lipid synthesis‐related genes . In turn, SREBP‐1 expression can be directly regulated by the phosphatidylinositol 3‐kinase (PI3K) –protein kinase B ( AKT ) pathway, which plays a crucial role in glucose and lipid metabolism mediating interactions between the liver and immune cells . Therefore, activating the PI3K – AKT pathway can induce the expression and activation of SREBP‐1 by controlling its nuclear localization and thereby promoting its transcriptional activity.…”

“…15 In turn, SREBP-1 expression can be directly regulated by the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT) pathway, which plays a crucial role in glucose and lipid metabolism mediating interactions between the liver and immune cells. 16 Therefore, activating the PI3K-AKT pathway can induce the expression and activation of SREBP-1 by controlling its nuclear localization and thereby promoting its transcriptional activity.…”