Treatment of acetaminophen-induced acute liver failure in the mouse with conditionally immortalized human hepatocytes

Nguyen, Tuan Huy; Mai, Gang; Villiger, Peter M.; Oberholzer, José; Salmon, Patrick; Morel, Philippe; Bühler, Léo H.; Trono, Didier

doi:10.1016/j.jhep.2005.05.036

Cited by 54 publications

(57 citation statements)

References 31 publications

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“…1). Second, we investigated immortalized human hepatocytes (a kind gift of Dr. D. Trono) and obtained the same results as for HepG2 cells (data not shown) (41). Third, we studied the expression of 11␤-HSD1 mRNA and activity in TNF-␣-TG, an analysis revealing that the effect observed in vitro is also present in vivo.…”

Section: Discussionmentioning

confidence: 93%

Tumor necrosis factor-α upregulates 11β-hydroxysteroid dehydrogenase type 1 expression by CCAAT/enhancer binding protein-β in HepG2 cells

Ignatova¹,

Kostadinova²,

Goldring³

et al. 2009

American Journal of Physiology-Endocrinology and Metabolism

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The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyzes the conversion of inactive to active glucocorticoids. 11β-HSD1 plays a crucial role in the pathogenesis of obesity and controls glucocorticoid actions in inflammation. Several studies have demonstrated that TNF-α increases 11β-HSD1 mRNA and activity in various cell models. Here, we demonstrate that mRNA and activity of 11β-HSD1 is increased in liver tissue from transgenic mice overexpressing TNF-α, indicating that this effect also occurs in vivo. To dissect the molecular mechanism of this increase, we investigated basal and TNF-α-induced transcription of the 11β-HSD1 gene ( HSD11B1) in HepG2 cells. We found that TNF-α acts via p38 MAPK pathway. Transient transfections with variable lengths of human HSD11B1 promoter revealed highest activity with or without TNF-α in the proximal promoter region (−180 to +74). Cotransfection with human CCAAT/enhancer binding protein-α (C/EBPα) and C/EBPβ-LAP expression vectors activated the HSD11B1 promoter with the strongest effect within the same region. Gel shift and RNA interference assays revealed the involvement of mainly C/EBPα, but also C/EBPβ, in basal and only of C/EBPβ in the TNF-α-induced HSD11B1 expression. Chromatin immunoprecipitation assay confirmed in vivo the increased abundance of C/EBPβ on the proximal HSD11B1 promoter upon TNF-α treatment. In conclusion, C/EBPα and C/EBPβ control basal transcription, and TNF-α upregulates 11β-HSD1, most likely by p38 MAPK-mediated increased binding of C/EBPβ to the human HSD11B1 promoter. To our knowledge, this is the first study showing involvement of p38 MAPK in the TNF-α-mediated 11β-HSD1 regulation, and that TNF-α stimulates enzyme activity in vivo.

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Section: Discussionmentioning

confidence: 93%

Tumor necrosis factor-α upregulates 11β-hydroxysteroid dehydrogenase type 1 expression by CCAAT/enhancer binding protein-β in HepG2 cells

Ignatova¹,

Kostadinova²,

Goldring³

et al. 2009

American Journal of Physiology-Endocrinology and Metabolism

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“…The AGS cell line, a human gastric epithelial adenocarcinoma cell line, was obtained from the American Type Culture Collection and maintained in RPMI 1640 GlutaMAX supplemented with 10% FBSi and 1% APS solution. Immortalized human hepatocytes (IHH; clone 10.3) were provided by Dr. T. H. Nguyen (INSERM, University Hospital, Nantes, France) and maintained in DMEM-F12, as described (30). Cells (0.5 ϫ 10 6 ) were placed in 75-cm 2 flasks (Nunc) and incubated at 37°C, 5% CO 2 , and 95% humidity.…”

Section: Cell Linesmentioning

confidence: 99%

Hepatocytes and IL-15: A Favorable Microenvironment for T Cell Survival and CD8+ T Cell Differentiation

Correia

Cardoso

Pereira³

et al. 2009

The Journal of Immunology

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Human intrahepatic lymphocytes are enriched in CD1d-unrestricted T cells coexpressing NKR. Although the origin of this population remains controversial, it is possible to speculate that the hepatic microenvironment, namely epithelial cells or the cytokine milieu, may play a role in its shaping. IL-15 is constitutively expressed in the liver and has a key role in activation and survival of innate and tissue-associated immune cells. In this in vitro study, we examined whether hepatocyte cell lines and/or IL-15 could play a role in the generation of NK-like T cells. The results show that both HepG2 cells and a human immortalized hepatocyte cell line increase survival and drive basal proliferation of T cells. In addition, IL-15 was capable of inducing Ag-independent up-regulation of NKR, including NKG2A, Ig-like receptors, and de novo expression of CD56 and NKp46 in CD8+CD56− T cells. In conclusion, our study suggests that hepatocytes and IL-15 create a favorable microenvironment for T cells to growth and survive. It can be proposed that the increased percentage of intrahepatic nonclassical NKT cells could be in part due to a local CD8+ T cell differentiation.

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“…Immortalization of human primary hepatocytes was generated by transduction with lentiviral vectors coding The aims of the present study were to evaluate in vitro functions of isolated hepatocytes after immortalizafor SV 40 large T antigen, Bmi-1, and telomerase in collaboration with Dr. T. Nguyen and Prof. Trono tion and encapsulation, and in vivo the impact of their transplantation on the regeneration of native liver cells (EPFL) (33). in a rodent model of ALF.…”

Section: Introductionmentioning

confidence: 99%

Transplantation of Encapsulated Hepatocytes during Acute Liver Failure Improves Survival without Stimulating Native Liver Regeneration

et al. 2011

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The aim of this study was to evaluate the effects of intraperitoneal transplantation of encapsulated human hepatocytes on liver metabolism and regeneration of mice with acute liver failure. Primary human hepatocytes were immortalized using lentiviral vectors coding for antiapoptotic genes and microencapsulated using alginate-polylysine polymers. In vitro, immortalized human hepatocytes showed low, but stable, synthetic and catabolitic functions over time, when compared to primary hepatocytes. In vivo, mice with acute liver failure and transplanted with encapsulated immortalized human hepatocytes had a significantly improved survival and biochemical profile, compared to mice transplanted with empty capsules. Serum levels of cytokines implicated in liver regeneration were lower in mice transplanted with hepatocytes compared to mice receiving empty capsules. This decrease was significant for IL-6 and HGF at 3 h. Measurement of liver regeneration showed no significant difference between mice transplanted with hepatocytes compared to control groups. Intraperitoneal transplantation of encapsulated immortalized hepatocytes significantly improved survival of mice with acute liver failure by providing metabolic support and without modifying liver regeneration. The lower levels of cytokines implicated in liver regeneration suggest that the metabolic support provided by the encapsulated hepatocytes reduced the inflammatory stress on the liver and herein decreased the regenerative trigger on residual hepatocytes. These data emphasize that metabolic function and regeneration of hepatocytes are two distinct aspects that need to be studied and approached separately during acute liver failure.

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Treatment of acetaminophen-induced acute liver failure in the mouse with conditionally immortalized human hepatocytes

Cited by 54 publications

References 31 publications

Tumor necrosis factor-α upregulates 11β-hydroxysteroid dehydrogenase type 1 expression by CCAAT/enhancer binding protein-β in HepG2 cells

Tumor necrosis factor-α upregulates 11β-hydroxysteroid dehydrogenase type 1 expression by CCAAT/enhancer binding protein-β in HepG2 cells

Hepatocytes and IL-15: A Favorable Microenvironment for T Cell Survival and CD8+ T Cell Differentiation

Transplantation of Encapsulated Hepatocytes during Acute Liver Failure Improves Survival without Stimulating Native Liver Regeneration

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