Abstract
Stimulation of human epithelial cells with IL-1 (10 ng/ml) + UVB radiation results in sustained NFκB activation caused by continuous IKKβ phosphorylation. We have recently published a strictly reduced ordinary differential equation model elucidating the involved mechanisms. Here, we compare model extensions for low IL-1 doses (0.5 ng/ml), where delayed IKKβ phosphorylation is observed. The extended model including a positive regulatory element, most likely auto-ubiquitination of TRAF6, reproduces the observed experimental data most convincingly. The extension is shown to be consistent with the original model and contains very sensitive processes which may serve as potential intervention targets.
Highlights
The transcription factor NFB is of central importance in inflammation and anti-apoptotic signaling
NFB is converted into a pro-apoptotic factor upon stimulation with IL-1 + ultraviolet-B radiation (UVB)
The persistence of this effect is ensured by sustained NFB activity [2] caused by sustained phosphorylation of IKKb resulting in instant phosphorylation and proteasomal degradation of newly synthesized IBa
Summary
The transcription factor NFB is of central importance in inflammation and anti-apoptotic signaling. Modeling Each of the three potential mechanisms delaying the signaling cascade following low doses of IL-1 is modeled as a separate building block (see Figure 2). The other extensions only perform about as well as the original model in terms of AICc. The TRAF extension convincingly reproduces the experimental data and especially the signal delay (Figure 3), and a biological counterpart to this mechanism exists within the IL-1 signaling cascade.
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