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

Tomasz Lipniacki, Krzysztof Puszynski, Pawel Paszek, Allan R. Brasier, Marek Kimmel

Research output: Contribution to journalArticle

50 Citations (Scopus)

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.

Original languageEnglish (US)
Article number376
JournalBMC Bioinformatics
Volume8
DOIs
StatePublished - Oct 9 2007

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Tumor Necrosis Factor
Activation
Genes
Chemical activation
Robustness
Cell
Pathogens
Amplification
Ligands
Switches
Gene
Cell Surface Receptors
Cell death
Immune Response
Translocation
Viruses
Gene expression
Transcriptional Activation
Switch
Tissue

ASJC Scopus subject areas

  • Medicine(all)
  • Structural Biology
  • Applied Mathematics

Cite this

Single TNFα trimers mediating NF-κB activation : Stochastic robustness of NF-κB signaling. / Lipniacki, Tomasz; Puszynski, Krzysztof; Paszek, Pawel; Brasier, Allan R.; Kimmel, Marek.

In: BMC Bioinformatics, Vol. 8, 376, 09.10.2007.

Research output: Contribution to journalArticle

Lipniacki, Tomasz ; Puszynski, Krzysztof ; Paszek, Pawel ; Brasier, Allan R. ; Kimmel, Marek. / Single TNFα trimers mediating NF-κB activation : Stochastic robustness of NF-κB signaling. In: BMC Bioinformatics. 2007 ; Vol. 8.
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