Instytut Podstawowych Problemów Techniki

Streszczenie:

We present an integrated dynamical cross-talk model of the epithelial innate immune reponse (IIR) incorporating RIG-I and TLR3 as the two major pattern recognition receptors (PRR) converging on the RelA and IRF3 transcriptional effectors. bioPN simulations reproduce biologically relevant gene-and protein abundance measurements in response to time course, gene silencing and dose-response perturbations both at the population and single cell level. Our computational predictions suggest that RelA and IRF3 are under auto- and cross-regulation. We predict, and confirm experimentally, that RIG-I mRNA expression is controlled by IRF7. We also predict the existence of a TLR3-dependent, IRF3-independent transcription factor (or factors) that control(s) expression of MAVS, IRF3 and members of the IKK family. Our model confirms the observed dsRNA dose-dependence of oscillatory patterns in single cells, with periods of 1–3 hr. Model fitting to time series, matched by knockdown data suggests that the NF-κB module operates in a different regime (with different coefficient values) than in the TNFα-stimulation experiments. In future studies, this model will serve as a foundation for identification of virus-encoded IIR antagonists and examination of stochastic effects of viral replication.

Our model generates simulated time series, which reproduce the noisy oscillatory patterns of activity (with 1–3 hour period) observed in individual cells. Our work supports the hypothesis that the IIR is a phenomenon that emerged by evolution despite highly variable responses at an individual cell level.

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Streszczenie:

Nuclear factors p53 and NF-kB control many physiological processes including cell cycle arrest, DNA repair, apoptosis, death, innate and adaptive immune responses, and inflammation. There are numerous pathways linking these systems and there is a bulk of evidence for cooperation as well as for antagonisms between p53 and NF-kB. In this theoretical study, the authors use earlier models of p53 and NF-kB systems and construct a crosstalk model of p53–NF-kB network in order to explore the consequences of the two-way coupling, in which NF-kB upregulates the transcription of p53, whereas in turn p53 attenuates transcription of NF-kB inhibitors IkBa and A20. We consider a number of protocols in which cells are stimulated by tumour necrosis factor-a (TNFa) (that activates NF-kB pathway) and/or gamma irradiation (that activates p53 pathway). The authors demonstrate that NF-kB may have both anti- and pro-apoptotic roles. TNFa stimulation, preceding DNA damaging irradiation, makes cells more resistant to irradiation-induced apoptosis, whereas the same TNFa stimulation, when preceded by irradiation, increases the apoptotic cell fraction. The finding suggests that diverse roles of NF-kB in apoptosis and cancer could be related to the dynamical context of activation of p53 and NF-kB pathways.

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