Description:
<jats:sec><jats:label /><jats:p>Gut‐derived bacterial lipopolysaccharides (<jats:styled-content style="fixed-case">LPS</jats:styled-content>) stimulate the secretion of tumour necrosis factor (<jats:styled-content style="fixed-case">TNF</jats:styled-content>) from liver macrophages (<jats:styled-content style="fixed-case">MC</jats:styled-content>s), liver sinusoidal endothelial cells (<jats:styled-content style="fixed-case">LSEC</jats:styled-content>s) and hepatic stellate cells (<jats:styled-content style="fixed-case">HSC</jats:styled-content>s), which control the acute phase response in hepatocytes through activation of the <jats:styled-content style="fixed-case">NF</jats:styled-content>‐κB pathway. The individual and cooperative impact of nonparenchymal cells on this clinically relevant response has not been analysed in detail due to technical limitations. To gain an integrative view on this complex inter‐ and intracellular communication, we combined a multiscale mathematical model with quantitative, time‐resolved experimental data of different primary murine liver cell types. We established a computational model for <jats:styled-content style="fixed-case">TNF</jats:styled-content>‐induced <jats:styled-content style="fixed-case">NF</jats:styled-content>‐κB signalling in hepatocytes, accurately describing dose‐responsiveness for physiologically relevant cytokine concentrations. <jats:styled-content style="fixed-case">TNF</jats:styled-content> secretion profiles were quantitatively measured for all nonparenchymal cell types upon <jats:styled-content style="fixed-case">LPS</jats:styled-content> stimulation. This novel approach allowed the analysis of individual and collective paracrine <jats:styled-content style="fixed-case">TNF</jats:styled-content>‐mediated <jats:styled-content style="fixed-case">NF</jats:styled-content>‐κB induction in hepatocytes, revealing strongest effects of <jats:styled-content style="fixed-case">MC</jats:styled-content>s and <jats:styled-content style="fixed-case">LSEC</jats:styled-content>s on hepatocellular <jats:styled-content style="fixed-case">NF</jats:styled-content>‐κB signalling. Simulations suggest that both cell types act together to maximize the <jats:styled-content style="fixed-case">NF</jats:styled-content>‐κB pathway response induced by low <jats:styled-content style="fixed-case">LPS</jats:styled-content> concentrations (0.1 and 1 ng/mL). Higher <jats:styled-content style="fixed-case">LPS</jats:styled-content> concentrations (≥ 5 ng/mL) induced sufficient <jats:styled-content style="fixed-case">TNF</jats:styled-content> levels from <jats:styled-content style="fixed-case">MC</jats:styled-content>s or <jats:styled-content style="fixed-case">LSEC</jats:styled-content>s to induce a strong and nonadjustable pathway response. Importantly, these simulations also revealed that the initial cytokine secretion (1–2 h after stimulation) rather than final <jats:styled-content style="fixed-case">TNF</jats:styled-content> level (10 h after stimulation) defines the hepatocellular <jats:styled-content style="fixed-case">NF</jats:styled-content>‐κB response. This raises the question whether the current experimental standard of single high‐dose cytokine administration is suitable to mimic <jats:italic>in vivo</jats:italic> cytokine exposure.</jats:p></jats:sec><jats:sec><jats:title>Database</jats:title><jats:p>The computational models described in this manuscript are available in the <jats:styled-content style="fixed-case">JWS</jats:styled-content> database via the following link: <jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="https://jjj.bio.vu.nl/database/beuke">https://jjj.bio.vu.nl/database/beuke</jats:ext-link></jats:p></jats:sec>