Interleukin-1 beta Enhances FasL-Induced Caspase-3/-7 Activity without Increasing Apoptosis in Primary Mouse Hepatocytes: e115603

• Published in: PloS one Vol. 9; no. 12
• Main Authors: Lutz, Anna, Sanwald, Julia, Thomas, Maria, Feuer, Ronny, Sawodny, Oliver, Ederer, Michael, Borner, Christoph, Humar, Matjaz, Merfort, Irmgard
• Format: Journal Article
• Language: English
• Published: 01.12.2014
• ISSN: 1932-6203
• DOI: 10.1371/journal.pone.0115603

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 beta 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 beta 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 beta and FasL treatment enhanced cytochrome c release. Surprisingly, despite increased caspase-3/-7 activation, FasL-induced cell death was reduced by IL-1 beta pre-treatment. This protective effect was independent of JNK1/2, Bim or Bid. Furthermore, elevated caspase-3/-7 activity upon IL-1 beta and FasL treatment did not result in enhanced PARP cleavage. The protective effect of IL-1 beta was seen after 3 h of pre-incubation, indicating an anti-apoptotic transcriptional response. Indeed, NF- Kappa B DNA binding was increased in response to IL-1 beta plus FasL and gene-expression profiling of NF- Kappa 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.