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.
Highlights
NF-kB Regulatory System Innate immunity forms the first line of defense against pathogens
The key modification is the inclusion of autocrine regulation via TNFa which leads to the positive feedback loop and qualitatively changes dynamics of cells characterized by sizable TNFa synthesis
The presence of the negative feedback loop together with the delay introduced by the mRNA transcription, protein translation and cytoplasmic to nuclear transport induces oscillatory responses to tonic TNFa stimulation
Summary
NF-kB Regulatory System Innate immunity forms the first line of defense against pathogens. Cells detect pathogens with their membrane and cytoplasmic receptors This leads to the activation of transcription factors from the NF-kB, IRF and AP-1 families. These factors jointly regulate the activity of several hundred genes responsible for inflammation, antiviral protection, proliferation and apoptosis. They induce the production of proinflammatory cytokines like IL-1, TNFa, as well as IFN-a and IFN-ß. Secretion of these cytokines leads to the second phase of the cellular innate immune response in cells that have not yet encountered the pathogen. The focus is on the analysis of TNFa autocrine regulation in the NF-kB pathway
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