| First Author | Lutz A | Year | 2014 |
| Journal | PLoS One | Volume | 9 |
| Issue | 12 | Pages | e115603 |
| PubMed ID | 25551609 | Mgi Jnum | J:225368 |
| Mgi Id | MGI:5693190 | Doi | 10.1371/journal.pone.0115603 |
| Citation | Lutz A, et al. (2014) Interleukin-1beta enhances FasL-induced caspase-3/-7 activity without increasing apoptosis in primary mouse hepatocytes. PLoS One 9(12):e115603 |
| abstractText | 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-1beta 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-1beta depleted the anti-apoptotic Bcl-2 protein pool and thus shifted hepatocytes to mitochondrial type II apoptosis following Fas activation. As a consequence, IL-1beta and FasL treatment enhanced cytochrome c release. Surprisingly, despite increased caspase-3/-7 activation, FasL-induced cell death was reduced by IL-1beta pre-treatment. This protective effect was independent of JNK1/2, Bim or Bid. Furthermore, elevated caspase-3/-7 activity upon IL-1beta and FasL treatment did not result in enhanced PARP cleavage. The protective effect of IL-1beta was seen after 3 h of pre-incubation, indicating an anti-apoptotic transcriptional response. Indeed, NF-kappaB DNA binding was increased in response to IL-1beta plus FasL and gene-expression profiling of NF-kappaB 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. |
