Interleukin-1β Enhances FasL-Induced Caspase-3/-7 Activity without Increasing Apoptosis in Primary Mouse Hepatocytes


Sustained inflammation may increase the susceptibility of hepatocytes to apoptotic cell death and therefore exacerbate liver damage. Here we report that the pro-inflammatory cytokine IL-1β sensitizes primary murine hepatocytes to Fas ligand (FasL)-induced caspase-3/-7 activity. This process was dependent on JNK1/2 and the BH3-only proteins Bim and Bid. Mathematical modeling revealed that incubation of hepatocytes with IL-1β depleted the anti-apoptotic Bcl-2 protein pool and thus shifted hepatocytes to mitochondrial type II apoptosis following Fas activation. As a consequence, IL-1β and FasL treatment enhanced cytochrome c release. Surprisingly, despite increased caspase-3/-7 activation, FasL-induced cell death was reduced by IL-1β pre-treatment. This protective effect was independent of JNK1/2, Bim or Bid. Furthermore, elevated caspase-3/-7 activity upon IL-1β and FasL treatment did not result in enhanced PARP cleavage. The protective effect of IL-1β was seen after 3 h of pre-incubation, indicating an anti-apoptotic transcriptional response. Indeed, NF-κB DNA binding was increased in response to IL-1β plus FasL and gene-expression profiling of NF-κB regulated genes revealed a transcriptional and translational upregulation of the caspase-8 inhibitor A20. A mathematical model was developed to explain the contradictious occurrence of both increased caspase-3/-7 activity and elevated cell viability by including a heterogeneous distribution of Bcl-2 proteins and variations in Fas signaling resulting in different subpopulations of hepatocytes.


Projects: A2.2: Regulation of pro-apoptotic and anti-apoptotic responses in hepato...

PLoS ONE 9(12) : e115603
31st Dec 2014

Anna Lutz, Julia Sanwald, Maria Thomas, Ronny Feuer, Oliver Sawodny, Michael Ederer, Christoph Borner, Matjaz Humar, Irmgard Merfort

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[Anna Lutz] [Julia Sanwald] [Maria Thomas] [Ronny Feuer] [Oliver Sawodny]

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Views: 1901
  • Created: 23rd Jan 2015 at 09:58
  • Last updated: 23rd Jan 2015 at 10:00

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