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A Systems Biology Study on NFκB Signaling in Primary Mouse Hepatocytes

Abstract:

The cytokine tumor necrosis factor-alpha (TNFα) is one of the key factors during the priming phase of liver regeneration as well as in hepatocarcinogenesis. TNFα activates the nuclear factor κ-light-chain-enhancer of activated B cells (NFκB) signaling pathway and contributes to the conversion of quiescent hepatocytes to activated hepatocytes that are able to proliferate in response to growth factor stimulation. Different mathematical models have been previously established for TNFα/NFκB signaling in the context of tumor cells. Combining these mathematical models with time-resolved measurements of expression and phosphorylation of TNFα/NFκB pathway constituents in primary mouse hepatocytes revealed that an additional phosphorylation step of the NFκB isoform p65 has to be considered in the mathematical model in order to sufficiently describe the dynamics of pathway activation in the primary cells. Also, we addressed the role of basal protein turnover by experimentally measuring the degradation rate of pivotal players in the absence of TNFα and including this information in the model. To elucidate the impact of variations in the protein degradation rates on TNFα/NFκB signaling on the overall dynamic behavior we used global sensitivity analysis that accounts for parameter uncertainties and showed that degradation and translation of p65 had a major impact on the amplitude and the integral of p65 phosphorylation. Finally, our mathematical model of TNFα/NFκB signaling was able to predict the time-course of the complex formation of p65 and of the inhibitor of NFκB (IκB) in primary mouse hepatocytes, which was experimentally verified. Hence, we here present a mathematical model for TNFα/NFκB signaling in primary mouse hepatocytes that provides an important basis to quantitatively disentangle the complex interplay of multiple factors in liver regeneration and tumorigenesis.

23293603

Projects: A2.1: Multi-level regulation of signalling pathways important for primin..., A2.4: Linking signalling pathways regulating liver regeneration and orga..., B1.2: Reciprocal effect of cell-cell communication on information proces...

Front Physiol
Front Physiol 3: 466
31st Dec 2012

Federico Pinna, Sven Sahle, Katharina Beuke, Michaela Bissinger, Selcan Tuncay, Lorenz A D'Alessandro, Ralph Gauges, Andreas Raue, Jens Timmer, Ursula Klingmüller, Peter Schirmacher, Ursula Kummer, Kai Breuhahn

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[Federico Pinna] [Sven Sahle] [Katharina Beuke] [Lorenza D'Alessandro] [Andreas Raue]
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Cell and Intercellular
Views: 1708
  • Created: 16th Jan 2013 at 08:49
  • Last updated: 24th Oct 2013 at 16:15

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