Accumulating data suggest that hepatic tolerance, initially demonstrated by spontaneous acceptance of liver allografts in many species, results from an immune regulatory activity occurring in the liver. However, the responsible cellular and molecular components have not been completely understood. We have recently described profound T cell inhibitory activity of hepatic stellate cells (HSCs) in vitro. In this study, we demonstrate in vivo evidence of immune modulatory activity of HSCs in mice using an islet transplantation model. Cotransplanted HSCs effectively protected islet allografts from rejection, forming a multilayered capsule, which reduced allograft immunocyte infiltrates by enhancement of apoptotic death. The immune modulation by HSCs appeared to be a local effect, and regulated by inducible expression of B7-H1, an inhibitory molecule of B7 family. This may reflect an intrinsic mechanism of immune inhibition mediated by liver-derived tissue cells. H epatic tolerance was initially recognized by spontaneous acceptance of liver allografts in a number of species. 1-4 Our laboratory focused on the mechanistic insights into liver transplant tolerance in mice and demonstrated that it is not attributable to a deletion of T cell clones specific to donor antigens, because lymphocytes isolated from tolerant mice respond well to donor antigen stimulation in vitro. 5 Whereas histological findings are notable for an abundance of CD4 and CD8 T cell infiltrates during the first week after transplantation, they are rapidly diminished via apoptotic death. [6][7][8] Similarly, in a nontransplant model, after injection of a specific antigenic peptide into TCR transgenic mice, deletion of specific CD8 ϩ T cells from the periphery was observed, as they accumulated in the liver and underwent subsequent apoptosis. 9 Combined, these results suggest a regulatory mechanism residing in the liver that may be responsible for its immune modulation. 10 However, the cellular components of the liver responsible for this are not completely understood.We have recently demonstrated that activated hepatic stellate cells (HSCs) effectively inhibit T cell responses in vitro, which is mediated by induction of T cell apoptosis. 11 Thus, subsequently studying whether HSCs can exert immune regulatory activities in vivo is logical. However, it is difficult to obtain direct evidence in the liver because approaches to specifically inhibit the effect of HSCs have not been defined. In this study, we used an islet allograft transplant model and demonstrated that cotransplantation with HSCs effectively protected islet allografts from rejection by forming a multi-layered immune barrier around the islets and reducing infiltrating T cells. Interestingly, HSCs isolated from B7-H1 knockout (KO) mice lost the protective effect on co-transplanted islet
Purpose: To unravel the role of interleukin (IL)-6 and insulinlike growth factor (IGF)-I receptor (IGFIR) in expressing stemnessrelated properties and to evaluate the prognostic values of pluripotent transcription factor OCT4/NANOG, and IGFIR in hepatocellular carcinoma (HCC).Experimental Design: Serum levels of IL6 were detected using ELISA assays (n ¼ 120). The effects of IL6/IGFI on stemness expression in HCC were examined using OCT4/ NANOG promoter luciferase reporter, RNA interference, secondary sphere formation, side population, and xenograft animal models. The OCT4/NANOG protein and phospho-IGFI receptor (p-IGFIR) in tissues were detected by Western blotting (n ¼ 8) and immunohistochemical staining (n ¼ 85). OCT4, NANOG, and IGFIR expression levels in tissues (n ¼ 191) were analyzed by real-time qRT-PCR and was correlated with early tumor recurrence using the Kaplan-Meier survival analysis.Results: A high positive correlation between the expression levels of OCT4/NANOG and IGFIR/p-IGFIR in human HCC tissues was observed. The concurrent expression of OCT4/ NANOG/IGFIR was mostly confined to hepatitis B virus (HBV)-related HCC (HBV-HCC) and was significantly correlated with early tumor recurrence. High serum levels of IL6 were significantly correlated with high OCT4/NANOG expression. IL6 stimulated an autocrine IGFI/IGFIR expression STAT3 dependently, which stimulated stemness-related properties in both the cell lines and the xenografted mouse tumors. The inhibition of IGFIR activation by either RNA interference or by treatment with the inhibitor picropodophyllin (PPP) significantly suppressed the IL6-induced stemness-related properties both in vitro and in vivo.Conclusions: The expression of pluripotency-related genes is associated with early tumor recurrence and is regulated by IL6-induced IGF/IGFIR activation, particularly in HBV-HCC.
Proliferation of hepatic stellate cells (HSCs) plays a key role in the pathogenesis of liver fibrosis. Induction of HSC apoptosis by natural products is considered an effective strategy for treating liver fibrosis. Herein, the apoptotic effects of 7,20-epoxy-ent-kaurane (oridonin), a diterpenoid isolated from Rabdosia rubescens, and its underlying mechanisms were investigated in rat HSC cell line, HSC-T6. We found that oridonin inhibited cell viability of HSC-T6 in a concentration-dependent manner. Oridonin induced a reduction in mitochondrial membrane potential and increases in caspase 3 activation, subG1 phase, and DNA fragmentation. These apoptotic effects of oridonin were completely reversed by thiol antioxidants, N-acetylcysteine (NAC) and glutathione monoethyl ester. Moreover, oridonin increased production of reactive oxygen species (ROS), which was also inhibited by NAC. Significantly, oridonin reduced intracellular glutathione (GSH) level in a concentrationand time-dependent fashion. Additionally, oridonin induced phosphorylations of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 OPEN ACCESSMolecules 2014, 19 3328 mitogen-activated protein kinase (MAPK). NAC prevented the activation of MAPKs in oridonin-induced cells. However, selective inhibitors of MAPKs failed to alter oridonin-induced cell death. In summary, these results demonstrate that induction of apoptosis in HSC-T6 by oridonin is associated with a decrease in cellular GSH level and increase in ROS production.
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