TNFR1 determines progression of chronic liver injury in the IKK gamma/Nemo genetic model

F.J. Cubero; A. Singh; E. Borkham-Kamphorst; Y.A. Nevzorova; M. Al Masaoudi; U. Haas; M.V. Boekschoten; N. Gassler; R. Weiskirchen; M. Muller; C. Liedtke; C. Trautwein

doi:10.1038/cdd.2013.112

TNFR1 determines progression of chronic liver injury in the IKK gamma/Nemo genetic model

F.J. Cubero, A. Singh, E. Borkham-Kamphorst, Y.A. Nevzorova, M. Al Masaoudi, U. Haas, M.V. Boekschoten, N. Gassler, R. Weiskirchen, M. Muller, C. Liedtke, C. Trautwein

Nutrition, Metabolism and Genomics

Research output: Contribution to journal › Article › Academic › peer-review

33 Citations (Scopus)

Abstract

Death receptor-mediated hepatocyte apoptosis is implicated in a wide range of liver diseases including viral and alcoholic hepatitis, ischemia/reperfusion injury, fulminant hepatic failure, cholestatic liver injury, as well as cancer. Deletion of NF-kappa B essential modulator in hepatocytes (IKK gamma/Nemo) causes spontaneous progression of TNF-mediated chronic hepatitis to hepatocellular carcinoma (HCC). Thus, we analyzed the role of death receptors including TNFR1 and TRAIL in the regulation of cell death and the progression of liver injury in IKK gamma/Nemo-deleted livers. We crossed hepatocyte-specific IKK gamma/Nemo knockout mice (Nemo(Delta hepa)) with constitutive TNFR1(-/-) and TRAIL(-/-) mice. Deletion of TNFR1, but not TRAIL, decreased apoptotic cell death, compensatory proliferation, liver fibrogenesis, infiltration of immune cells as well as pro-inflammatory cytokines, and indicators of tumor growth during the progression of chronic liver injury. These events were associated with diminished JNK activation. In contrast, deletion of TNFR1 in bone-marrow-derived cells promoted chronic liver injury. Our data demonstrate that TNF- and not TRAIL signaling determines the progression of IKK gamma/Nemo-dependent chronic hepatitis. Additionally, we show that TNFR1 in hepatocytes and immune cells have different roles in chronic liver injury-a finding that has direct implications for treating chronic liver disease.

Original language	English
Pages (from-to)	1580-1592
Journal	Cell Death and Differentiation
Volume	20
Issue number	11
DOIs	https://doi.org/10.1038/cdd.2013.112
Publication status	Published - 2013

Keywords

nf-kappa-b
necrosis-factor receptor
mice lacking type-1
nemo/ikk-gamma
deficient mice
hepatocellular-carcinoma
embryonic lethality
controlled-trial
knockout mice
target genes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/cdd.2013.112

TNFR1 controls apoptosis and chronic liver disease in hepatocyte-specific IKKγ (Nemo) mice.
Singh, A. (Creator), Cubero, F. J. (Creator), Borkham-Kamphorst, E. (Creator), Nevzorova, Y. A. (Creator), Al Masaoudi, M. (Creator), Boekschoten, M. (Creator), Gassler, N. (Creator), Weiskirchen, R. (Creator), Luedde, T. (Creator), Heikenwalder, M. (Creator), Muller, M. (Creator), Liedtke, C. (Creator) & Trautwein, C. (Creator), Wageningen University, 3 Sept 2014
https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE33161
Dataset

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Cubero, F. J., Singh, A., Borkham-Kamphorst, E., Nevzorova, Y. A., Al Masaoudi, M., Haas, U., Boekschoten, M. V., Gassler, N., Weiskirchen, R., Muller, M., Liedtke, C., & Trautwein, C. (2013). TNFR1 determines progression of chronic liver injury in the IKK gamma/Nemo genetic model. Cell Death and Differentiation, 20(11), 1580-1592. https://doi.org/10.1038/cdd.2013.112

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abstract = "Death receptor-mediated hepatocyte apoptosis is implicated in a wide range of liver diseases including viral and alcoholic hepatitis, ischemia/reperfusion injury, fulminant hepatic failure, cholestatic liver injury, as well as cancer. Deletion of NF-kappa B essential modulator in hepatocytes (IKK gamma/Nemo) causes spontaneous progression of TNF-mediated chronic hepatitis to hepatocellular carcinoma (HCC). Thus, we analyzed the role of death receptors including TNFR1 and TRAIL in the regulation of cell death and the progression of liver injury in IKK gamma/Nemo-deleted livers. We crossed hepatocyte-specific IKK gamma/Nemo knockout mice (Nemo(Delta hepa)) with constitutive TNFR1(-/-) and TRAIL(-/-) mice. Deletion of TNFR1, but not TRAIL, decreased apoptotic cell death, compensatory proliferation, liver fibrogenesis, infiltration of immune cells as well as pro-inflammatory cytokines, and indicators of tumor growth during the progression of chronic liver injury. These events were associated with diminished JNK activation. In contrast, deletion of TNFR1 in bone-marrow-derived cells promoted chronic liver injury. Our data demonstrate that TNF- and not TRAIL signaling determines the progression of IKK gamma/Nemo-dependent chronic hepatitis. Additionally, we show that TNFR1 in hepatocytes and immune cells have different roles in chronic liver injury-a finding that has direct implications for treating chronic liver disease.",

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AU - Cubero, F.J.

AU - Singh, A.

AU - Borkham-Kamphorst, E.

AU - Nevzorova, Y.A.

AU - Al Masaoudi, M.

AU - Haas, U.

AU - Boekschoten, M.V.

AU - Gassler, N.

AU - Weiskirchen, R.

AU - Muller, M.

AU - Liedtke, C.

AU - Trautwein, C.

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N2 - Death receptor-mediated hepatocyte apoptosis is implicated in a wide range of liver diseases including viral and alcoholic hepatitis, ischemia/reperfusion injury, fulminant hepatic failure, cholestatic liver injury, as well as cancer. Deletion of NF-kappa B essential modulator in hepatocytes (IKK gamma/Nemo) causes spontaneous progression of TNF-mediated chronic hepatitis to hepatocellular carcinoma (HCC). Thus, we analyzed the role of death receptors including TNFR1 and TRAIL in the regulation of cell death and the progression of liver injury in IKK gamma/Nemo-deleted livers. We crossed hepatocyte-specific IKK gamma/Nemo knockout mice (Nemo(Delta hepa)) with constitutive TNFR1(-/-) and TRAIL(-/-) mice. Deletion of TNFR1, but not TRAIL, decreased apoptotic cell death, compensatory proliferation, liver fibrogenesis, infiltration of immune cells as well as pro-inflammatory cytokines, and indicators of tumor growth during the progression of chronic liver injury. These events were associated with diminished JNK activation. In contrast, deletion of TNFR1 in bone-marrow-derived cells promoted chronic liver injury. Our data demonstrate that TNF- and not TRAIL signaling determines the progression of IKK gamma/Nemo-dependent chronic hepatitis. Additionally, we show that TNFR1 in hepatocytes and immune cells have different roles in chronic liver injury-a finding that has direct implications for treating chronic liver disease.

AB - Death receptor-mediated hepatocyte apoptosis is implicated in a wide range of liver diseases including viral and alcoholic hepatitis, ischemia/reperfusion injury, fulminant hepatic failure, cholestatic liver injury, as well as cancer. Deletion of NF-kappa B essential modulator in hepatocytes (IKK gamma/Nemo) causes spontaneous progression of TNF-mediated chronic hepatitis to hepatocellular carcinoma (HCC). Thus, we analyzed the role of death receptors including TNFR1 and TRAIL in the regulation of cell death and the progression of liver injury in IKK gamma/Nemo-deleted livers. We crossed hepatocyte-specific IKK gamma/Nemo knockout mice (Nemo(Delta hepa)) with constitutive TNFR1(-/-) and TRAIL(-/-) mice. Deletion of TNFR1, but not TRAIL, decreased apoptotic cell death, compensatory proliferation, liver fibrogenesis, infiltration of immune cells as well as pro-inflammatory cytokines, and indicators of tumor growth during the progression of chronic liver injury. These events were associated with diminished JNK activation. In contrast, deletion of TNFR1 in bone-marrow-derived cells promoted chronic liver injury. Our data demonstrate that TNF- and not TRAIL signaling determines the progression of IKK gamma/Nemo-dependent chronic hepatitis. Additionally, we show that TNFR1 in hepatocytes and immune cells have different roles in chronic liver injury-a finding that has direct implications for treating chronic liver disease.

KW - nf-kappa-b

KW - necrosis-factor receptor

KW - mice lacking type-1

KW - nemo/ikk-gamma

KW - deficient mice

KW - hepatocellular-carcinoma

KW - embryonic lethality

KW - controlled-trial

KW - knockout mice

KW - target genes

U2 - 10.1038/cdd.2013.112

DO - 10.1038/cdd.2013.112

M3 - Article

SN - 1350-9047

VL - 20

SP - 1580

EP - 1592

JO - Cell Death and Differentiation

JF - Cell Death and Differentiation

IS - 11

ER -

TNFR1 determines progression of chronic liver injury in the IKK gamma/Nemo genetic model

Abstract

Keywords

UN SDGs

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Datasets

TNFR1 controls apoptosis and chronic liver disease in hepatocyte-specific IKKγ (Nemo) mice.

Cite this