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Spontaneous NF-?B activation by autocrine TNF? signaling: a computational analysis.

ABSTRACT: NF-?B 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-?B inducible inhibitors, I?B? and A20, which assure oscillatory responses, and by positive feedback loops arising due to the paracrine and autocrine regulation via TNF?, IL-1 and other cytokines. We study the NF-?B 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 TNF? and its receptor TNFR1, may exhibit sustained cytoplasmic-nuclear NF-?B oscillations which start spontaneously due to stochastic fluctuations. In A20-deficient cells even a small TNF? expression rate qualitatively influences system kinetics, leading to long-lasting NF-?B activation in response to a short-pulsed TNF? stimulation. As a consequence, cells with impaired A20 expression or increased TNF? secretion rate are expected to have elevated NF-?B 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-?B. There is growing evidence that A20 mutations correlate with several types of lymphomas and elevated TNF? 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 TNF? secretion, which at high levels overcomes the antiapoptotic action of NF-?B. It is thus tempting to speculate that some cancers of deregulated NF-?B signaling may be prone to the pathogen-induced apoptosis.

SUBMITTER: Pekalski J

PROVIDER: S-EPMC3855823 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Spontaneous NF-κB activation by autocrine TNFα signaling: a computational analysis.

Pękalski Jakub J Zuk Pawel J PJ Kochańczyk Marek M Junkin Michael M Kellogg Ryan R Tay Savaş S Lipniacki Tomasz T

PloS one 20131111 11

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 deter ...[more]

PMID: 24324544

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Project description:Growing evidences suggest that sustained neuroinflammation, caused by microglia overactivation, is implicated in the development and aggravation of several neurological and psychiatric disorders. In some pathological conditions, microglia produce increased levels of cytotoxic and inflammatory mediators, such as tumor necrosis factor alpha (TNF-α), which can reactivate microglia in a positive feedback mechanism. However, specific molecular mediators that can be effectively targeted to control TNF-α-mediated microglia overactivation, are yet to be uncovered. In this context, we aim to identify novel TNF-α-mediated micro(mi)RNAs and to dissect their roles in microglia activation, as well as to explore their impact on the cellular communication with neurons. A miRNA microarray, followed by RT-qPCR validation, was performed on TNF-α-stimulated primary rat microglia. Gain- and loss-of-function in vitro assays and proteomic analysis were used to dissect the role of miR-342 in microglia activation. Co-cultures of microglia with hippocampal neurons, using a microfluidic system, were performed to understand the impact on neurotoxicity. Stimulation of primary rat microglia with TNF-α led to an upregulation of Nos2, Tnf, and Il1b mRNAs. In addition, ph-NF-kB p65 levels were also increased. miRNA microarray analysis followed by RT-qPCR validation revealed that TNF-α stimulation induced the upregulation of miR-342. Interestingly, miR-342 overexpression in N9 microglia was sufficient to activate the NF-kB pathway by inhibiting BAG-1, leading to increased secretion of TNF-α and IL-1β. Conversely, miR-342 inhibition led to a strong decrease in the levels of these cytokines after TNF-α activation. In fact, both TNF-α-stimulated and miR-342-overexpressing microglia drastically affected neuron viability. Remarkably, increased levels of nitrites were detected in the supernatants of these co-cultures. Globally, our findings show that miR-342 is a crucial mediator of TNF-α-mediated microglia activation and a potential target to tackle microglia-driven neuroinflammation.

Dataset Information

Spontaneous NF-?B activation by autocrine TNF? signaling: a computational analysis.

Publications

Spontaneous NF-κB activation by autocrine TNFα signaling: a computational analysis.

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