A systematic survey of the response of a model NF-κB signalling pathway to TNFα stimulation

White's lab established that strong, continuous stimulation with tumour necrosis factor-alpha (TNF alpha) can induce sustained oscillations in the subcellular localisation of the transcription factor nuclear factor kappa B (NF-kappa B). But the intensity of the TNF alpha signal varies substantially, from picomolar in the blood plasma of healthy organisms to nanomolar in diseased states. We report on a systematic survey using computational bifurcation theory to explore the relationship between the intensity of TNF alpha stimulation and the existence of sustained NF-kappa B oscillations. Using a deterministic model developed by Ashall et al. in 2009, we find that the system's responses to TNF alpha are characterised by a supercritical Hopf bifurcation point: above a critical intensity of TNF alpha the system exhibits sustained oscillations in NF-kappa B localisation. For TNF alpha below this critical value, damped oscillations are observed. This picture depends, however, on the values of the model's other parameters. When the values of certain reaction rates are altered the response of the signalling pathway to TNFa stimulation changes: in addition to the sustained oscillations induced by high-dose stimulation, a second oscillatory regime appears at much lower doses. Finally, we define scores to quantify the sensitivity of the dynamics of the system to variation in its parameters and use these scores to establish that the qualitative dynamics are most sensitive to the details of NF-kappa B mediated gene transcription. (C) 2011 Elsevier Ltd. All rights reserved.