title: Quantitative and integrative analysis of paracrine hepatocyte activation by nonparenchymal cells upon lipopolysaccharide induction.
abstract: Gut-derived bacterial lipopolysaccharides (LPS) stimulate the secretion of tumour necrosis factor (TNF) from liver macrophages (MCs), liver sinusoidal endothelial cells (LSECs) and hepatic stellate cells (HSCs), which control the acute phase response in hepatocytes through activation of the NF-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 TNF-induced NF-κB signalling in hepatocytes, accurately describing dose-responsiveness for physiologically relevant cytokine concentrations. TNF secretion profiles were quantitatively measured for all nonparenchymal cell types upon LPS stimulation. This novel approach allowed the analysis of individual and collective paracrine TNF-mediated NF-κB induction in hepatocytes, revealing strongest effects of MCs and LSECs on hepatocellular NF-κB signalling. Simulations suggest that both cell types act together to maximize the NF-κB pathway response induced by low LPS concentrations (0.1 and 1 ng/mL). Higher LPS concentrations (≥ 5 ng/mL) induced sufficient TNF levels from MCs or LSECs 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 TNF level (10 h after stimulation) defines the hepatocellular NF-κB response. This raises the question whether the current experimental standard of single high-dose cytokine administration is suitable to mimic in vivo cytokine exposure.
  
  
  
  The computational models described in this manuscript are available in the JWS database via the following link: https://jjj.bio.vu.nl/database/beuke.
authors.affiliation: Department of Modeling of Biological Processes, COS Heidelberg/BIOQUANT, Heidelberg University, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Beuke
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA, USA.
authors.forename: Frank A
authors.initials: FA
authors.lastname: Schildberg
authors.affiliation: Institute of Pathology, University Hospital of Heidelberg, Germany.
authors.forename: Federico
authors.initials: F
authors.lastname: Pinna
authors.affiliation: Clinic for Gastroenterology, Heinrich-Heine-University of Düsseldorf, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Albrecht
authors.affiliation: Molecular Hepatology, Department of Medicine II, Medical Faculty at Mannheim, Heidelberg University, Germany.
authors.forename: Roman
authors.initials: R
authors.lastname: Liebe
authors.affiliation: Institute of Pathology, University Hospital of Heidelberg, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Bissinger
authors.affiliation: Institute of Pathology, University Hospital of Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Schirmacher
authors.affiliation: Molecular Hepatology, Department of Medicine II, Medical Faculty at Mannheim, Heidelberg University, Germany.
authors.forename: Steven
authors.initials: S
authors.lastname: Dooley
authors.affiliation: Clinic for Gastroenterology, Heinrich-Heine-University of Düsseldorf, Germany.
authors.forename: Johannes G
authors.initials: JG
authors.lastname: Bode
authors.affiliation: Institute of Molecular Immunology and Experimental Oncology, München Rechts der Isar, Technische Universität München, Germany.
authors.forename: Percy A
authors.initials: PA
authors.lastname: Knolle
authors.affiliation: Department of Modeling of Biological Processes, COS Heidelberg/BIOQUANT, Heidelberg University, Germany.
authors.forename: Ursula
authors.initials: U
authors.lastname: Kummer
authors.affiliation: Institute of Pathology, University Hospital of Heidelberg, Germany.
authors.forename: Kai
authors.initials: K
authors.lastname: Breuhahn
authors.affiliation: Department of Modeling of Biological Processes, COS Heidelberg/BIOQUANT, Heidelberg University, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Sahle
mesh_terms: D000818:Animals; D022781:Hepatocytes / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D019899:Paracrine Communication / Q000187:drug effects; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*
chemical_list: D008070:Lipopolysaccharides; C498143:RELA protein, human; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha
keywords: ODE model; cytokine secretion; hepatic stellate cells; inflammation; lipopolysaccharide; liver; liver sessile macrophages; liver sinusoidal endothelial cells; nuclear factor kappa B; tumour necrosis factor