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• W2610301492 abstract "Gut-derived bacteria enter the liver via the portal vein where they induce an innate immune response leading to inflammation. Lipopolysaccharide, a part the bacterial cell wall component endotoxin, functions as stimulus for toll-like receptors in non-parenchymal liver cells leading to secretion of di- verse cytokines. Among these cytokines tumor necrosis factor (TNF) is one of the first to be produced. It binds to the TNF receptors of hepatocytes and activates NF-κB signalling. The transcription factor NF-κB enhances gene expressions of acute phase proteins. Its signalling primes hepatocytes for cell proliferation.In this work, I have studied NF-κB signalling in hepatocytes in various ways, using computational models trained and validated with experimental data from primary murine cells. First, I extended an ODE model of canonical NF- κB signalling to include the experimentally validated influence of p38 MAPK signalling on this signalling pathway. Additionally, by including the receptor level to the model, I ensured an accurate description of dose response mea- surements for the main pathway components. This was especially important for the second part of this work, where I used the ODE intra-hepatocellular model to investigate the influence of different non-parenchymal cells on hepatocytes in the liver. By combining information on cell abundance and cell size, and experimental TNF secretion profiles in response to LPS with this ODE model, I was able to establish for the first time a computational model combing all liver cell types relevant to LPS-induced TNF secretion and intra-hepatocellular NF-κB signalling. I could show that liver resident macrophages and liver sinusoidal endothelial cells produce the most TNF in response to LPS. Furthermore, my simulations showed that not the final lev- els of TNF regulate the in vivo response, rather the initial cytokine increase defines how strongly NF-κB signalling is activated in hepatocytes. As a third part I converted the ODE model into a PDE model, which describes possible temporal and spatial aspects of single cell microscopy measurements. I was able to show that the relevant reaction parameters of the ODE model could be used for PDE simulations to describe experimental data on the localisa- tion of fluorescently labeled NF-κB molecules after TNF stimulation. Further- more, I could show that the dynamics observed on a population-based level were comparable to those observable on a single cell level.These new insights into NF-κB signalling in the liver may change experi- mental procedures with respect to cytokine administration when analysing inflammation. Furthermore, the new multi-cellular model can serve as a basis for simulating the influence of non-parenchymal cells on hepatocytes under various experimental conditions." @default.
• W2610301492 created "2017-05-12" @default.
• W2610301492 creator A5001458341 @default.
• W2610301492 date "2016-01-01" @default.
• W2610301492 modified "2023-09-24" @default.
• W2610301492 title "TNF-induced NF-κB signal transduction in the liver" @default.
• W2610301492 doi "https://doi.org/10.11588/heidok.00020853" @default.
• W2610301492 hasPublicationYear "2016" @default.
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