Single TNFα trimers mediating NF-κ B activation: stochastic robustness of NF-κ B signaling

Abstract

BackgroundThe NF-κB regulatory network controls innate immune response by transducing variety of pathogen-derived and cytokine stimuli into well defined single-cell gene regulatory events.ResultsWe analyze the network by means of the model combining a deterministic description for molecular species with large cellular concentrations with two classes of stochastic switches: cell-surface receptor activation by TNFα ligand, and IκBα and A20 genes activation by NF-κB molecules. Both stochastic switches are associated with amplification pathways capable of translating single molecular events into tens of thousands of synthesized or degraded proteins. Here, we show that at a low TNFα dose only a fraction of cells are activated, but in these activated cells the amplification mechanisms assure that the amplitude of NF-κB nuclear translocation remains above a threshold. Similarly, the lower nuclear NF-κB concentration only reduces the probability of gene activation, but does not reduce gene expression of those responding.ConclusionThese two effects provide a particular stochastic robustness in cell regulation, allowing cells to respond differently to the same stimuli, but causing their individual responses to be unequivocal. Both effects are likely to be crucial in the early immune response: Diversity in cell responses causes that the tissue defense is harder to overcome by relatively simple programs coded in viruses and other pathogens. The more focused single-cell responses help cells to choose their individual fates such as apoptosis or proliferation. The model supports the hypothesis that binding of single TNFα ligands is sufficient to induce massive NF-κB translocation and activation of NF-κB dependent genes.

Stochastic effects and bistability in T cell receptor signaling

“…This situation is similar to the case of NF-κB responses stimulated by low doses of TNFα, where we showed that noise at the level of receptor activation causes single cell responses to be much different from the average trajectory (Lipniacki et al, 2007). The stochasticity means that cells do not follow their deterministic trajectories converging to a steady state, but may occasionally jump between the basins of attraction of two possible states.…”

Oscillations and bistability in the stochastic model of p53 regulation

“…It is natural to expect that reactions involving small number of molecules, but associated with some amplification pathways, are the main source of the overall stochasticity (Lipniacki et al, 2007). The first candidate is the expression of p53-responsive gene.…”

Physiological levels of TNFα stimulation induce stochastic dynamics of NF-κB responses in single living cells

“…A population-level analysis suggested that at low TNF doses, cells produce damped responses that are homogenous across the population (Cheong et al, 2006). By contrast, a theoretical study by Lipniacki and colleagues suggested that system activation at low doses might be very stochastic; however, a full NF-B response might be achieved even at the picomolar TNF concentration (proposed to be due to the binding of a single TNF trimer) (Lipniacki et al, 2007). This theoretical analysis predicted the existence of a threshold for system activation associated with an event within a TNF-R1-IKK transduction pathway.…”

“…2). At these low doses, it might be necessary for receptor activation events to occur above a threshold for a response to be generated (Lipniacki et al, 2007). To test this hypothesis, cells were exposed to a short pulse (5 minutes) at a range of TNF concentrations.…”

“…Cheong and co-workers (Cheong et al, 2006) used ordinary differential equations based on the law of mass action, which were unable to simulate the intrinsic stochasticity of single cell responses. A theoretical model by Lipniacki and colleagues (Lipniacki et al, 2007) captured some heterogeneity of the system responses (in particular the random delay to the initial activation at low doses), by incorporating noise into the activation of TNF-R1 receptors and transcription of NF-B feedback genes. However, this model could not predict the maintenance of the robust 100 minute oscillations or the reduction in the N:C amplitude that was observed in these experiments (Lipniacki et al, 2007).…”