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CYLD deletion triggers nuclear factor-κB-signaling and increases cell death resistance in murine hepatocytes

Toni Urbanik1, Bruno Christian Koehler1, Laura Wolpert1

  • 1Toni Urbanik, Bruno Christian Koehler, Laura Wolpert, Christin Elßner, Anna-Lena Scherr, Nicole Kautz, Stefan Welte, Dirk Jäger, Henning Schulze-Bergkamen, National Center for Tumor Diseases, Department of Medical Oncology, University Clinic of Heidelberg, 69120 Heidelberg, Baden-Wuerrtemberg, Germany.

World Journal of Gastroenterology
|December 11, 2014
PubMed
Abstract

Insights

CYLD deficiency protects against liver injury by reducing hepatocyte apoptosis. This occurs through enhanced NF-κB signaling, which increases anti-apoptotic protein expression, making hepatocytes less sensitive to death receptor-mediated cell death.

Area of Science:

  • Hepatology and Immunology
  • Molecular Biology
  • Cell Death Research

Background:

  • Receptor-mediated apoptosis plays a critical role in liver injury.
  • The CYLD (CYLD Lysine 63 Deubiquitinase) gene's function in hepatocyte apoptosis is not fully understood.
  • Understanding CYLD's role is crucial for developing therapeutic strategies against acute liver injury.

Purpose of the Study:

  • To investigate the role of CYLD in receptor-mediated apoptosis of murine hepatocytes.
  • To analyze the impact of CYLD deficiency on acute liver injury models.

Main Methods:

  • Utilized CYLD knockout (CYLD(-/-)) and wild-type (WT) mice in CD95- (Jo2) and tumor necrosis factor-α (TNF-α) [D-GalN/lipopolysaccharide (LPS)] induced liver injury models.
  • Assessed liver injury via serum transaminases (ALT, AST) and histological analysis.
  • Quantified apoptosis using cleaved PARP staining, Western blotting for activated caspases, and MTT assays on primary hepatocytes.

Main Results:

  • CYLD(-/-) mice exhibited significantly reduced apoptosis sensitivity in both liver injury models, with lower ALT and AST levels compared to WT mice.
  • CYLD deficiency led to increased anti-apoptotic nuclear factor-kappa B (NF-κB) signaling in hepatocytes.
  • Isolated CYLD(-/-) primary murine hepatocytes (PMH) showed increased expression of anti-apoptotic proteins (Bcl-2, XIAP, cIAP1/2, survivin, c-FLIP) and were less sensitive to TNF-α and CD95-ligand induced cell death.

Conclusions:

  • CYLD acts as a key regulator of apoptotic cell death in murine hepatocytes.
  • CYLD controls NF-κB-dependent anti-apoptotic signaling pathways.
  • CYLD deficiency confers protection against acute liver injury by modulating hepatocyte apoptosis.
Keywords:
ApoptosisCD95CYLDLiverNuclear factor-κBTumor necrosis factor-α

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