<i>c‐Myc</i> partially mediates IFN<i>γ</i>‐induced apoptosis in the primary hepatocyte

McCullough, Christian T.; Tura, Benjamin J; Harrison, David J.

doi:10.1111/j.1365-2613.2006.00521.x

Cited by 8 publications

(5 citation statements)

References 40 publications

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“…Fas is constitutively expressed on hepatocytes and its engagement rapidly results in hepatocyte apoptosis in vivo (38). Moreover, the direct apoptotic effects of IFN-γ on murine hepatocytes may require FasL/Fas interactions (39). With these considerations in mind, we hypothesized that liver injury in Tgfb1 −/− mice is Fas dependent.…”

Section: Resultsmentioning

confidence: 99%

End-Organ Damage in a Mouse Model of Fulminant Liver Inflammation Requires CD4+ T Cell Production of IFN-γ but Is Independent of Fas

Robinson¹,

Wang²,

Cripps³

et al. 2009

The Journal of Immunology

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Fulminant inflammation in the liver is often accompanied by the accumulation of IFN-γ-producing T cells. The BALB/c-Tgfb1−/− mouse exhibits extensive, spontaneously developing necroinflammation in the liver, accompanied by the accumulation of IFN-γ-producing CD4+ and CD8+ T cells. Liver damage depends on the presence of an intact Ifng gene. We determined the relevant cellular source(s) of IFN-γ. In Tgfb1−/− liver, CD4+ T cells were more numerous than CD8+ T cells and NK cells, and produced more IFN-γ. Depletion of CD4+ T cells eliminated both the elevation in plasma IFN-γ and aspartate aminotransferase, whereas depletion of CD8+ T cells did not. Rag1−/−Tgfb1−/− mice exhibited neither IFN-γ elevation nor tissue damage, indicating that NK cells are not sufficient. IFN-γ was required for strong overexpression of class II genes but not for CD4+ T cell activation, oligoclonal expansion, or accumulation in the liver. The T cell inhibitory molecule PD-L1 was strongly expressed in Tgfb1−/− livers, ruling out a lack of PD-L1 expression as an explanation for aberrant liver T cell activation. Finally, whereas Tgfb1−/− CD4+ T cells overexpressed Fas ligand, hepatocellular damage was observed in Faslpr/lprTgfb1−/− mice, indicating that liver pathology is Fas independent. We conclude that liver damage in this model of fulminant autoimmune hepatitis is driven by CD4+ T cell production of IFN-γ, is independent of both CD8+ T cells and the Fas ligand/Fas pathway, and is not explained by a lack of PD-L1 expression.

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Section: Resultsmentioning

confidence: 99%

End-Organ Damage in a Mouse Model of Fulminant Liver Inflammation Requires CD4+ T Cell Production of IFN-γ but Is Independent of Fas

Robinson¹,

Wang²,

Cripps³

et al. 2009

The Journal of Immunology

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“…CBDL has been used as an animal model of chronic liver injury because it duplicates the retention of toxic bile acids during human cholestatic liver disease. The LHBDL model is used to study prolonged liver fibrogenesis independent of liver failure 27. This model of LHBDL allows a comparison of the injured ligated left lobe and the nonligated right lobe.…”

Section: Discussionmentioning

confidence: 99%

“…The c‐Myc oncogene, which is induced during BDL,25 functions as a positive regulator of cell proliferation and growth. Paradoxically, c‐Myc can also result in the sensitization of cells to apoptosis under conditions of hepatocyte injury 27. Max serves as an obligate heterodimerization partner for Myc, allowing it to bind E‐box consensus sequences to activate transcription 11.…”

Section: Discussionmentioning

confidence: 99%

Switch from Mnt‐Max to Myc‐Max induces p53 and cyclin D1 expression and apoptosis during cholestasis in mouse and human hepatocytes†

Yang

et al. 2009

Hepatology

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Background and rationale Toxic bile acids induce hepatocyte apoptosis for which p53 and cyclin D1 have been implicated as underlying mediators. Both p53 and cyclin D1 are targets of c-Myc, which is also up-regulated in cholestasis. Myc and Mnt use Max as a cofactor for DNA binding. Myc-Max typically activates transcription via E-box binding. Mnt-Max also binds E-box sequence but serves as a repressor and inhibits the enhancer activity of Myc-Max. The current work tested the hypothesis that the switch from Mnt-Max to Myc-Max is responsible for p53 and cyclin D1 up-regulation and apoptosis during cholestasis. Results Following common bile duct ligation or left hepatic bile duct ligation, the expression of p53, c-Myc and cyclin D1 increased markedly while Mnt expression decreased. Nuclear binding activity of Myc to E-box element of p53 and cyclin D1 increased, while that of Mnt decreased in a time-dependent fashion. Lithocolic acid (LCA) treatment of primary human hepatocytes and HuH-7 cells induced a similar switch from Mnt to Myc, increased p53 and cyclin D1 promoter activity, endogenous p53 and cyclin D1 expression and apoptosis. Blocking c-Myc induction in HuH-7 cells prevented the LCA-mediated increase in p53 and cyclin D1 expression and reduced apoptosis. Lowering Mnt expression further enhanced LCA’s inductive effect on p53 and cyclin D1. Bile duct ligated mice treated with lentivirus harboring c-myc siRNA were protected from hepatic induction of p53 and cyclin D1, switch in Mnt to Myc nuclear binding to E-box, and hepatocyte apoptosis. Conclusions The switch from Mnt to Myc during BDL and in hepatocytes treated with LCA is responsible for the induction in p53 and cyclin D1 expression and contributes to apoptosis.

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“…Furthermore, several cytokines that are secreted in response to liver damage such as IFNγ, TNFα, IL-2, IL-4 and IL-6 contribute to NK cell activation (Notas et al 2009). Interestingly, NK and NK-T cells are a major source of interferon gamma (IFNγ) which has been shown to cause apoptosis of hepatocytes (Kano et al 1997; McCullough et al 2007). However, the significance of this report has been challenged by a recent study by Masson et al which demonstrated that dimethyl sulfoxide (DMSO, which was used as vehicle for the first study) and not acetaminophen, triggers activation and recruitment of NK cells in liver (Masson et al 2008).…”

Section: Structure and Cellular Components Of The Livermentioning

confidence: 99%

Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME

Hewitt²,

et al. 2013

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This review encompasses the most important advances in liver functions and hepatotoxicity and analyzes which mechanisms can be studied in vitro. In a complex architecture of nested, zonated lobules, the liver consists of approximately 80 % hepatocytes and 20 % non-parenchymal cells, the latter being involved in a secondary phase that may dramatically aggravate the initial damage. Hepatotoxicity, as well as hepatic metabolism, is controlled by a set of nuclear receptors (including PXR, CAR, HNF-4α, FXR, LXR, SHP, VDR and PPAR) and signaling pathways. When isolating liver cells, some pathways are activated, e.g., the RAS/MEK/ERK pathway, whereas others are silenced (e.g. HNF-4α), resulting in up- and downregulation of hundreds of genes. An understanding of these changes is crucial for a correct interpretation of in vitro data. The possibilities and limitations of the most useful liver in vitro systems are summarized, including three-dimensional culture techniques, co-cultures with non-parenchymal cells, hepatospheres, precision cut liver slices and the isolated perfused liver. Also discussed is how closely hepatoma, stem cell and iPS cell–derived hepatocyte-like-cells resemble real hepatocytes. Finally, a summary is given of the state of the art of liver in vitro and mathematical modeling systems that are currently used in the pharmaceutical industry with an emphasis on drug metabolism, prediction of clearance, drug interaction, transporter studies and hepatotoxicity. One key message is that despite our enthusiasm for in vitro systems, we must never lose sight of the in vivo situation. Although hepatocytes have been isolated for decades, the hunt for relevant alternative systems has only just begun.Electronic supplementary materialThe online version of this article (doi:10.1007/s00204-013-1078-5) contains supplementary material, which is available to authorized users.

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c‐Myc partially mediates IFNγ‐induced apoptosis in the primary hepatocyte

Cited by 8 publications

References 40 publications

End-Organ Damage in a Mouse Model of Fulminant Liver Inflammation Requires CD4+ T Cell Production of IFN-γ but Is Independent of Fas

End-Organ Damage in a Mouse Model of Fulminant Liver Inflammation Requires CD4+ T Cell Production of IFN-γ but Is Independent of Fas

Switch from Mnt‐Max to Myc‐Max induces p53 and cyclin D1 expression and apoptosis during cholestasis in mouse and human hepatocytes†

Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME

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