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RIPK1 protects from TNF-α-mediated liver damage during hepatitis
- Source :
- Cell Death and Disease, Cell Death and Disease, Nature Publishing Group, 2016, 7 (11), pp.e2462. ⟨10.1038/cddis.2016.362⟩, Cell Death & Disease, CELL DEATH & DISEASE, Cell Death and Disease, 2016, 7 (11), pp.e2462. ⟨10.1038/cddis.2016.362⟩
- Publication Year :
- 2016
- Publisher :
- HAL CCSD, 2016.
-
Abstract
- Cell death of hepatocytes is a prominent characteristic in the pathogenesis of liver disease, while hepatolysis is a starting point of inflammation in hepatitis and loss of hepatic function. However, the precise molecular mechanisms of hepatocyte cell death, the role of the cytokines of hepatic microenvironment and the involvement of intracellular kinases, remain unclear. Tumor necrosis factor alpha (TNF-alpha) is a key cytokine involved in cell death or survival pathways and the role of RIPK1 has been associated to the TNF-alpha-dependent signaling pathway. We took advantage of two different deficient mouse lines, the RIPK1 kinase dead knock-in mice (Ripk1K45A) and the conditional knockout mice lacking RIPK1 only in liver parenchymal cells (Ripk1LPC-KO), to characterize the role of RIPK1 and TNF-alpha in hepatitis induced by concanavalin A (ConA). Our results show that RIPK1 is dispensable for liver homeostasis under steady-state conditions but in contrast, RIPK1 kinase activity contributes to caspase-independent cell death induction following ConA injection and RIPK1 also serves as a scaffold, protecting hepatocytes from massive apoptotic cell death in this model. In the Ripk1LPC-KO mice challenged with ConA, TNF-alpha triggers apoptosis, responsible for the observed severe hepatitis. Mechanism potentially involves both TNF-independent canonical NF-kappa B activation, as well as TNF-dependent, but canonical NF-kappa B-independent mechanisms. In conclusion, our results suggest that RIPK1 kinase activity is a pertinent therapeutic target to protect liver against excessive cell death in liver diseases.
- Subjects :
- NF-KAPPA-B
Apoptosis
[SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC]
MOUSE HEPATOCYTES
Protective Agents
Models, Biological
Hepatitis
MURINE ACETAMINOPHEN TOXICITY
HEPATOCELLULAR-CARCINOMA
Medicine and Health Sciences
Concanavalin A
Animals
Homeostasis
IN-VIVO
Cells, Cultured
ComputingMilieux_MISCELLANEOUS
TUMOR-NECROSIS-FACTOR
INDUCED APOPTOSIS
Inflammation
Tumor Necrosis Factor-alpha
Biology and Life Sciences
[SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology
TNF Receptor-Associated Factor 2
A-INDUCED HEPATITIS
Mice, Inbred C57BL
Liver
Receptor-Interacting Protein Serine-Threonine Kinases
Hepatocytes
KINASE-ACTIVITY
Original Article
IL-33 EXPRESSION
Subjects
Details
- Language :
- English
- ISSN :
- 20414889
- Database :
- OpenAIRE
- Journal :
- Cell Death and Disease, Cell Death and Disease, Nature Publishing Group, 2016, 7 (11), pp.e2462. ⟨10.1038/cddis.2016.362⟩, Cell Death & Disease, CELL DEATH & DISEASE, Cell Death and Disease, 2016, 7 (11), pp.e2462. ⟨10.1038/cddis.2016.362⟩
- Accession number :
- edsair.pmid.dedup....5a5b6529ef12bdf32b43bc5ba92724c3