title: Single TNFalpha trimers mediating NF-kappaB activation: stochastic robustness of NF-kappaB signaling.
abstract: BACKGROUND
  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.
  
  
  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 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Institute of Fundamental Technological Research, Swietokrzyska 21, 00-049 Warsaw, Poland. tlipnia@ippt.gov.pl
authors.forename: Tomasz
authors.initials: T
authors.lastname: Lipniacki
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Puszynski
authors.forename: Pawel
authors.initials: P
authors.lastname: Paszek
authors.forename: Allan R
authors.initials: AR
authors.lastname: Brasier
authors.forename: Marek
authors.initials: M
authors.lastname: Kimmel
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000276:immunology; D019281:Dimerization; D004306:Dose-Response Relationship, Immunologic; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D020672:I-kappa B Proteins / Q000378:metabolism; D008024:Ligands; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D017711:Nonlinear Dynamics; D009685:Nuclear Envelope / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013269:Stochastic Processes; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000819:agonists / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D020672:I-kappa B Proteins; D008024:Ligands; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D051550:I-kappa B Kinase