Modeling time delay in the NFκB signaling pathway following low dose IL-1 stimulation

The transcription factor NFκB is of central importance in inflammation and anti-apoptotic signaling. Upon stimulation of human epithelial cells with IL-1, NFκB becomes activated due to proteasomal degradation of its cellular inhibitor IκBα. This process requires phosphorylation of IκBα by the upstream kinase IKKβ. Since sustained NFκB-dependent expression of anti-apoptotic genes contributes to the maintenance of a range of cancers, its activity is tightly regulated and terminated by a negative feedback loop, as NFκB promotes IκBα synthesis. Accordingly, various approaches to anti-cancer strategies involve inhibition of the NFκB signaling pathway [1].Interestingly, NFκB is converted into a pro-apoptotic factor upon stimulation with IL-1 + UVB. The persistence of this effect is ensured by sustained NFκB activity [2] caused by sustained phosphorylation of IKKβ resulting in instant phosphorylation and proteasomal degradation of newly synthesized IκBα. Chronic IKKβ phosphorylation, in turn, is due to UVB-induced inhibition of the responsible phosphatase PP2Ac [2]. We investigated the details of these processes using a systems biological approach, leading to the following ordinary differential equation model of IKKβ phosphorylation and dephosphorylation [3]:with [ILR](0) = 1, [ILRc](0) = 0, [IKKp](0) = 0, [PP2A](0) = 1, [IKK] = 1 - [IKKp]. By western blot analysis, we measure IKKp_obs = IKKp scale_IKK. The factor scale_IKK describes the unknown ratio between the strength of the IKKp band on the gel and the concentration of IKKp.The system variables describe the normalized concentrations of IL-1 receptor [ILR], IL-1 receptor complex [ILRc], phosphorylated and unphosphorylated IKKβ ([IKKp] and [IKK]), and PP2Ac [PP2A], the inputs il(t) and uv(t) describe IL-1 concentration and UVB radiation. Due to the normalization, all kinetic parameters of this model are given in s-1 except for ka (nM-1 s-1), since il(t) is given in nM.In the original model [3] the effects of the signali