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Interleukin-1? enhances FasL-induced caspase-3/-7 activity without increasing apoptosis in primary mouse hepatocytes.


ABSTRACT: 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-1? 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-1? depleted the anti-apoptotic Bcl-2 protein pool and thus shifted hepatocytes to mitochondrial type II apoptosis following Fas activation. As a consequence, IL-1? and FasL treatment enhanced cytochrome c release. Surprisingly, despite increased caspase-3/-7 activation, FasL-induced cell death was reduced by IL-1? pre-treatment. This protective effect was independent of JNK1/2, Bim or Bid. Furthermore, elevated caspase-3/-7 activity upon IL-1? and FasL treatment did not result in enhanced PARP cleavage. The protective effect of IL-1? was seen after 3 h of pre-incubation, indicating an anti-apoptotic transcriptional response. Indeed, NF-?B DNA binding was increased in response to IL-1? plus FasL and gene-expression profiling of NF-?B 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.

SUBMITTER: Lutz A 

PROVIDER: S-EPMC4281199 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Interleukin-1β enhances FasL-induced caspase-3/-7 activity without increasing apoptosis in primary mouse hepatocytes.

Lutz Anna A   Sanwald Julia J   Thomas Maria M   Feuer Ronny R   Sawodny Oliver O   Ederer Michael M   Borner Christoph C   Humar Matjaz M   Merfort Irmgard I  

PloS one 20141231 12


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 hepatocy  ...[more]

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