| First Author | Schlatter R | Year | 2011 |
| Journal | PLoS One | Volume | 6 |
| Issue | 4 | Pages | e18646 |
| PubMed ID | 21533085 | Mgi Jnum | J:172395 |
| Mgi Id | MGI:5007593 | Doi | 10.1371/journal.pone.0018646 |
| Citation | Schlatter R, et al. (2011) Modeling the TNFalpha-Induced Apoptosis Pathway in Hepatocytes. PLoS One 6(4):e18646 |
| abstractText | The proinflammatory cytokine TNFalpha fails to provoke cell death in isolated hepatocytes but has been implicated in hepatocyte apoptosis during liver diseases associated with chronic inflammation. Recently, we showed that TNFalpha is able to sensitize primary murine hepatocytes cultured on collagen to Fas ligand-induced apoptosis and presented a mathematical model of the sensitizing effect. Here, we analyze how TNFalpha induces apoptosis in combination with the transcriptional inhibitor actinomycin D (ActD). Accumulation of reactive oxygen species (ROS) in response to TNFR activation turns out to be critical for sustained activation of JNK which then triggers mitochondrial pathway-dependent apoptosis. In addition, the amount of JNK is strongly upregulated in a ROS-dependent way. In contrast to TNFalpha plus cycloheximide no cFLIP degradation is observed suggesting a different apoptosis pathway in which the Itch-mediated cFLIP degradation and predominantly caspase-8 activation is not involved. Time-resolved data of the respective pro- and antiapoptotic factors are obtained and subjected to mathematical modeling. On the basis of these data we developed a mathematical model which reproduces the complex interplay regulating the phosphorylation status of JNK and generation of ROS. This model was fully integrated with our model of TNFalpha/Fas ligand sensitizing as well as with a published NF-kappaB-model. The resulting comprehensive model delivers insight in the dynamical interplay between the TNFalpha and FasL pathways, NF-kappaB and ROS and gives an example for successful model integration. |
