Interleukin-1β Enhances FasL-Induced Caspase-3/-7 Activity without Increasing Apoptosis in Primary Mouse Hepatocytes
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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
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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- Created: 23rd Jan 2015 at 09:58
- Last updated: 23rd Jan 2015 at 10:00
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