- In hepatocytes and in macrophages, which mediate the inflammatory response in the liver upon challenge, the activation of the p38MAPK/MK2 pathway by IL-1β is important for the control of acute phase response as well as for liver regeneration upon damage. Little is known about key characteristics of this pathway in terms of concentration-dependent signal propagation and cell-type specific responses. Based on a mathematical model the present study provides evidence that signal transduction from IL-1β via p38MAPK to MK2 is characterized by a strong signal amplification. Quantification of the intracellular phosphorylation level of the residues Thr180 and Tyr182 of p38MAPK and Thr200 of MK2 reveals that in primary murine hepatocytes at maximum 11.3% of p38MAPK molecules and 36.5% of MK2 molecules are activated in IL-1β signaling. Furthermore, in silico analyses demonstrate that the kinase activity of p38MAPK determines the signal amplitude while phosphatase activity affects both signalIn hepatocytes and in macrophages, which mediate the inflammatory response in the liver upon challenge, the activation of the p38MAPK/MK2 pathway by IL-1β is important for the control of acute phase response as well as for liver regeneration upon damage. Little is known about key characteristics of this pathway in terms of concentration-dependent signal propagation and cell-type specific responses. Based on a mathematical model the present study provides evidence that signal transduction from IL-1β via p38MAPK to MK2 is characterized by a strong signal amplification. Quantification of the intracellular phosphorylation level of the residues Thr180 and Tyr182 of p38MAPK and Thr200 of MK2 reveals that in primary murine hepatocytes at maximum 11.3% of p38MAPK molecules and 36.5% of MK2 molecules are activated in IL-1β signaling. Furthermore, in silico analyses demonstrate that the kinase activity of p38MAPK determines the signal amplitude while phosphatase activity affects both signal amplitude and signal duration. In contrast to this in bone marrow derived macrophages at maximum only 4.5% of p38MAPK molecules and 17,2% of MK2 molecules are activated upon treatment with IL-1β, whereas quantification of p38MAPK and MK2 total protein reveals that the intracellular concentration in macrophages is approximately three times higher than in hepatocytes. We conclude that even with a lower percentage of activated p38MAPK and MK2 macrophages display comparable or even higher phosphorylation levels than hepatocytes. Hence, the mathematical model of this study reveals cell-type-specific differences concerning the response towards the treatment with IL-1β.…
