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Table 6 Predictions of the models for SKW 6.4 cells

From: Model composition through model reduction: a combined model of CD95 and NF-κB signaling pathways

The models behavior Experimental observations by Bentele et al.and predictions of the models
1 Experiments by Bentele et al.:
   − for 1 ng/ml of anti-CD95, PARP cleavage was not observed;
   − the measured death rate for 10 ng/ml of anti-CD95 was 20-30%.
   Original model (red):
   − the apoptotic threshold is 1.9 ng/ml;
   − cPARP concentration rises dramatically within an extremely narrow interval of anti-CD95 levels overcoming the apoptotic threshold.
   Composite model (blue):
   − the apoptotic threshold is 3.5 ng/ml;
   − cPARP concentration rises in a smooth manner along with the increase of anti-CD95 level.
2 Experiments by Bentele et al.: down-regulation of cFLIP in SKW 6.4 cells by addition of cyclohexamide resulted in cell death (40% for 1 day) already upon 1 ng/ml of anti-CD95. The level of cFLIP was decreased to 70%.
   Original (red) and composite (blue) models:
   − the apoptotic threshold is highly sensitive to the concentration of cFLIP;
   − decreasing the initial concentration of cFLIP by more than 51% and 49% for the original and composite models, respectively, leads to cell death upon stimulation by 1 ng/ml of anti-CD95.
3 Experiments by Bentele et al.: in the 10 ng/ml activation scenario, a significant increase of caspase-8 was observed after more than 4 hours.
   Original (red) and composite (blue) models: anti-CD95 concentrations which are slightly above the apoptotic threshold result in caspase-8 activation after a delay of many hours.
   The figure shows peak times of caspase-8 concentration exceeding 0.1% of the initial procaspase-8 level.
4 Original model:
   − low concentrations of IAP (less than 1 nM) result in complete cell death;
   − high concentrations of IAP prevent a significant increase of caspase-3 even for high concentrations of the ligand.
   Composite model:
   − low concentrations of IAP (less than 1 nM) block apoptosis for CD95L less than 0.3 nM;
   − high concentrations of CD95L lead to cell death.
   The figures show logarithmic dependence of the maximal caspases-3 concentration on initial values of IAP and CD95L.
  1. The simulation time was 2880 min (2 days) in all predictions. The apoptotic threshold in the prediction 1 is the concentration of anti-CD95 after which cPARP amount exceeds 10% of the initial PARP level.