Z Gastroenterol 2012; 50 - P4_02
DOI: 10.1055/s-0031-1295888

Dynamic model of IL–6 and IL–1beta dependent signalling in primary murine hepatocytes

U Albrecht 1, A Kulawik 1, A Raue 2, J Timmer 2, U Klingmüller 3, D Häussinger 1, JG Bode 1
  • 1Klinik für Gastroenterologie, Hepatologie und Infektiologie; Universitätsklinikum Düsseldorf, Düsseldorf
  • 2Institute of Physics, Freiburg
  • 3Systems Biology of Signal Transduction, Heidelberg

The hepatic inflammatory response is an important part of the host defence and also represents a critical regulatory event in hepatic liver regeneration. It is mainly orchestrated by a mediator based communication between the different cell types in the liver, including parenchymal cells and non-parenchymal cells, such as sessile liver macrophages (Kupffer cells). In this context, a cytokine mediated signal always depends on the background of co-acting factors and the type of target cells. In macrophages the interleukin–6 (IL–6) induced STAT3 (signal transducer and activator of transcription) activation is abrogated in the presence of LPS (lipopolysaccharide) or TNF-α (tumor necrosis factor), whereas in hepatocytes the STAT3 dependent signal transduction of IL–6 is abolished in the presence of IL–1β. This inhibitory effect is largely mediated by IL–1β dependent activation of the p38MAPK cascade.

Implementing a systems biology approach, a mathematical model has been generated which describes the crosstalk between the IL–1β mediated activation of the p38MAPK / MK2 cascade and the IL–6 induced activation of STAT3. Optimal parameter estimation fitting to quantitative data determined for activating phosphorylation of p38MAPK, MK2 and STAT3 requires the embedding of regulatory feedback loops to describe the time- and dose dependent kinetics. Model based perturbation experiments using MK2 deficient primary murine hepatocytes indicate that MK2 is the key molecule mediating the inhibitory effects of IL–1β on the STAT3-mediated signalling of IL–6 by internalisation of the gp130 receptor. Both dynamic ODE (ordinary differential equation) models were integrated horizontally, presenting a combined model on the intracellular hepatocellular scale.

Present goal of this study is to include qualitative and quantitative mediator patterns in macrophages, using BMDM (bone marrow derived macrophages) in order to link and extend the intracellular signalling model to intercellular communication.

Signalling - hepatocytes - interleukin - systems biology