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Open Access Research article

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

Tomasz Lipniacki1*, Krzysztof Puszynski3, Pawel Paszek24, Allan R Brasier5 and Marek Kimmel23

Author Affiliations

1 Institute of Fundamental Technological Research, Swietokrzyska 21, 00-049 Warsaw, Poland

2 Department of Statistics, Rice University, 6100 Main St. MS-138, Houston, TX 77005, USA

3 Institute of Automation, Silesian Technical University, 44-100 Gliwice, Poland

4 Centre for Cell Imaging, School of Biological Sciences, Bioscience Research Building, Crown St., University of Liverpool, Liverpool L69 7ZB, UK

5 Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555-1060, USA

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BMC Bioinformatics 2007, 8:376  doi:10.1186/1471-2105-8-376

Published: 9 October 2007

Abstract

Background

The 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.

Results

We 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.

Conclusion

These 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.