title: Spontaneous NF-κB activation by autocrine TNFα signaling: a computational analysis.
abstract: NF-κB is a key transcription factor that regulates innate immune response. Its activity is tightly controlled by numerous feedback loops, including two negative loops mediated by NF-κB inducible inhibitors, IκBα and A20, which assure oscillatory responses, and by positive feedback loops arising due to the paracrine and autocrine regulation via TNFα, IL-1 and other cytokines. We study the NF-κB system of interlinked negative and positive feedback loops, combining bifurcation analysis of the deterministic approximation with stochastic numerical modeling. Positive feedback assures the existence of limit cycle oscillations in unstimulated wild-type cells and introduces bistability in A20-deficient cells. We demonstrated that cells of significant autocrine potential, i.e., cells characterized by high secretion of TNFα and its receptor TNFR1, may exhibit sustained cytoplasmic-nuclear NF-κB oscillations which start spontaneously due to stochastic fluctuations. In A20-deficient cells even a small TNFα expression rate qualitatively influences system kinetics, leading to long-lasting NF-κB activation in response to a short-pulsed TNFα stimulation. As a consequence, cells with impaired A20 expression or increased TNFα secretion rate are expected to have elevated NF-κB activity even in the absence of stimulation. This may lead to chronic inflammation and promote cancer due to the persistent activation of antiapoptotic genes induced by NF-κB. There is growing evidence that A20 mutations correlate with several types of lymphomas and elevated TNFα secretion is characteristic of many cancers. Interestingly, A20 loss or dysfunction also leaves the organism vulnerable to septic shock and massive apoptosis triggered by the uncontrolled TNFα secretion, which at high levels overcomes the antiapoptotic action of NF-κB. It is thus tempting to speculate that some cancers of deregulated NF-κB signaling may be prone to the pathogen-induced apoptosis.
authors: Institute of Fundamental Technological Research, Polish Academy of Sciences, Warsaw, Poland ; Institute of Physical Chemistry, Polish Academy of Sciences, Warsaw, Poland.
authors: Jakub
authors: J
authors: Pękalski
authors: Pawel J
authors: PJ
authors: Zuk
authors: Marek
authors: M
authors: Kochańczyk
authors: Michael
authors: M
authors: Junkin
authors: Ryan
authors: R
authors: Kellogg
authors: Savaş
authors: S
authors: Tay
authors: Tomasz
authors: T
authors: Lipniacki
mesh_terms: D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D019295:Computational Biology; D003546:Cysteine Endopeptidases; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D007375:Interleukin-1; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D044767:Ubiquitin-Protein Ligases; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D003546:Cysteine Endopeptidases; C513261:Tnfaip3 protein, mouse