Single TNFalpha trimers mediating NF-kappaB activation: stochastic robustness of NF-kappaB signaling.

Lipniacki, Tomasz ORCID: 0000-0002-3488-2561, Puszynski, Krzysztof ORCID: 0000-0002-5546-4916, Paszek, Pawel ORCID: 0000-0002-0363-0716, Brasier, Allan R ORCID: 0000-0002-5012-4090 and Kimmel, Marek
(2007) Single TNFalpha trimers mediating NF-kappaB activation: stochastic robustness of NF-kappaB signaling. BMC bioinformatics, 8 (1). 376-.

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<h4>Background</h4>The NF-kappaB regulatory network controls innate immune response by transducing variety of pathogen-derived and cytokine stimuli into well defined single-cell gene regulatory events.<h4>Results</h4>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 TNFalpha ligand, and IkappaBalpha and A20 genes activation by NF-kappaB 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 TNFalpha dose only a fraction of cells are activated, but in these activated cells the amplification mechanisms assure that the amplitude of NF-kappaB nuclear translocation remains above a threshold. Similarly, the lower nuclear NF-kappaB concentration only reduces the probability of gene activation, but does not reduce gene expression of those responding.<h4>Conclusion</h4>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 TNFalpha ligands is sufficient to induce massive NF-kappaB translocation and activation of NF-kappaB dependent genes.

Item Type: Article
Additional Information: 20 pages (page numbers not for citation purposes). Published: 9 October 2007.
Uncontrolled Keywords: Nuclear Envelope, Animals, Humans, Tumor Necrosis Factor-alpha, NF-kappa B, Ligands, Stochastic Processes, Signal Transduction, Dose-Response Relationship, Immunologic, Gene Expression Regulation, Enzyme Activation, Biological Transport, Dimerization, Nonlinear Dynamics, I-kappa B Proteins, I-kappa B Kinase, Transcriptional Activation, NF-KappaB Inhibitor alpha
Subjects: ?? Q1 ??
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Divisions: Faculty of Health and Life Sciences > Institute of Life Courses and Medical Sciences > School of Medicine
Depositing User: Symplectic Admin
Date Deposited: 04 Nov 2008 12:36
Last Modified: 16 Mar 2024 14:08
DOI: 10.1186/1471-2105-8-376
Publisher's Statement : © 2007 Lipniacki et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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