title: IL-1β-induced and p38MAPK-dependent activation of the mitogen-activated protein kinase-activated protein kinase 2 (MK2) in hepatocytes: Signal transduction with robust and concentration-independent signal amplification.
abstract: The IL-1β induced activation of the p38MAPK/MAPK-activated protein kinase 2 (MK2) pathway in hepatocytes is important for control of the acute phase response and regulation of liver regeneration. Many aspects of the regulatory relevance of this pathway have been investigated in immune cells in the context of inflammation. However, very little is known about concentration-dependent activation kinetics and signal propagation in hepatocytes and the role of MK2. We established a mathematical model for IL-1β-induced activation of the p38MAPK/MK2 pathway in hepatocytes that was calibrated to quantitative data on time- and IL-1β concentration-dependent phosphorylation of p38MAPKand MK2 in primary mouse hepatocytes. This analysis showed that, in hepatocytes, signal transduction from IL-1β via p38MAPKto MK2 is characterized by strong signal amplification. Quantification of p38MAPKand MK2 revealed that, in hepatocytes, at maximum, 11.3% of p38MAPKmolecules and 36.5% of MK2 molecules are activated in response to IL-1β. The mathematical model was experimentally validated by employing phosphatase inhibitors and the p38MAPKinhibitor SB203580. Model simulations predicted an IC50of 1-1.2 μm for SB203580 in hepatocytes.In silicoanalyses and experimental validation demonstrated that the kinase activity of p38MAPKdetermines signal amplitude, whereas phosphatase activity affects both signal amplitude and duration. p38MAPKand MK2 concentrations and responsiveness toward IL-1β were quantitatively compared between hepatocytes and macrophages. In macrophages, the absolute p38MAPKand MK2 concentration was significantly higher. Finally, in line with experimental observations, the mathematical model predicted a significantly higher half-maximal effective concentration for IL-1β-induced pathway activation in macrophages compared with hepatocytes, underscoring the importance of cell type-specific differences in pathway regulation.
authors.affiliation: From the Department of Gastroenterology, Hepatology, and Infectious Disease, University Hospital, Heinrich Heine University, Moorenstraße 5, 40225 Düsseldorf, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Kulawik
authors.affiliation: the Institute of Physics, University of Freiburg, Hermann-Herder-Straße 3, 79104 Freiburg, Germany.|the BIOSS Centre for Biological Signaling Studies, University of Freiburg, Schänzlestraße 18, 79104 Freiburg, Germany.
authors.forename: Raphael
authors.initials: R
authors.lastname: Engesser
authors.affiliation: From the Department of Gastroenterology, Hepatology, and Infectious Disease, University Hospital, Heinrich Heine University, Moorenstraße 5, 40225 Düsseldorf, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Ehlting
authors.affiliation: the Institute of Physics, University of Freiburg, Hermann-Herder-Straße 3, 79104 Freiburg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Raue
authors.affiliation: From the Department of Gastroenterology, Hepatology, and Infectious Disease, University Hospital, Heinrich Heine University, Moorenstraße 5, 40225 Düsseldorf, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Albrecht
authors.affiliation: Molecular Structure Analysis and.
authors.forename: Bettina
authors.initials: B
authors.lastname: Hahn
authors.affiliation: Molecular Structure Analysis and.
authors.forename: Wolf-Dieter
authors.initials: WD
authors.lastname: Lehmann
authors.affiliation: the Institute of Physiological Chemistry, Hannover Medical School, 30625 Hannover, Germany, and.
authors.forename: Matthias
authors.initials: M
authors.lastname: Gaestel
authors.affiliation: Division of Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
authors.forename: Ursula
authors.initials: U
authors.lastname: Klingmüller
authors.affiliation: From the Department of Gastroenterology, Hepatology, and Infectious Disease, University Hospital, Heinrich Heine University, Moorenstraße 5, 40225 Düsseldorf, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Häussinger
authors.affiliation: the Institute of Physics, University of Freiburg, Hermann-Herder-Straße 3, 79104 Freiburg, Germany.|the BIOSS Centre for Biological Signaling Studies, University of Freiburg, Schänzlestraße 18, 79104 Freiburg, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Timmer
authors.affiliation: From the Department of Gastroenterology, Hepatology, and Infectious Disease, University Hospital, Heinrich Heine University, Moorenstraße 5, 40225 Düsseldorf, Germany, Johannes.Bode@med.uni-duesseldorf.de.
authors.forename: Johannes G
authors.initials: JG
authors.lastname: Bode
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D053583:Interleukin-1beta / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D008954:Models, Biological; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D007093:Imidazoles; D053583:Interleukin-1beta; D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D011725:Pyridines; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C587672:IL1B protein, mouse; C093642:SB 203580
keywords: MAPK; cell signaling; computational biology; hepatocyte; interleukin 1β; liver; macrophage; mathematical modeling; p38 MAPK; systems biology