(248e) Mathematical Model of Il-6 Signal Transduction in Hepatocytes

This paper presents a mathematical model for IL-6 (interleukin-6) signal transduction in hepatocytes. This work focuses on the role of IL-6 in the hepatic acute phase response. A kinetic model of signaling in hepatocytes stimulated by IL-6 has been developed. Signal transduction by the IL-6 family of cytokines involves the activation of two major pathways: the JAK (Janus-associated kinases)/ STAT (signal transducers and transcription factors) and the MAPK (mitogen-activated protein kinases) pathways [2, 3]. While the first pathway involves the activation of gp130 (glycoprotein 130), JAK and transcription factor STAT3, the MAPK pathway is linked to JAK/STAT by SHP-2 (domain containing tyrosine phosphatase 2) through gp130. The activation of SHP-2 is a crucial event for signaling through the MAPK pathway. In addition to acting as an adaptor protein for the MAPK pathway, SHP-2 acts as a phosphatase for the JAK/STAT pathway [4]. The dual role of SHP-2 suggests possible interactions between the two signaling pathways. However, the involvement of both JAK/STAT and MAPK pathways in IL-6 signaling has been studied only in few cases [5] and the interactions between the two pathways and the role played by SHP-2 in IL-6 signal transduction are not clearly understood. In this work, a kinetic model has been developed that considers signaling through both, i.e. the JAK/STAT and the MAPK, pathways. The developed model is used to analyze the interactions between the two pathways and to investigate the role of SHP-2 in signal transduction. In addition to down regulation by SHP2, SOCS3 (suppressor of cytokine signaling 3) also acts as inhibitor for signal transduction through the JAK/STAT pathway [1, 2, 3]. The influence of SOCS3 and SHP-2 on signaling induced by IL-6 is not independent of each other. SOCS3 influences the phosphorylation of SHP2 and through it has an effect on signaling through the MAPK pathway. The influence of SOCS3 on signal transduction has been evaluated in this work by simulation of the developed model.

The results obtained through simulations have been compared with available results from the literature and were found to predict behavior inline with the experimental studies found in the literature. The model shows that phosphorylated SHP-2 inhibits signal transduction through the JAK/STAT pathway. While SOCS3 acts as an inhibitor for the JAK/STAT pathway, it also down regulates the phosphorylation of SHP-2 and presumably inhibits signaling through the MAPK pathway. Further, it can be concluded from the presented results that SHP-2 and SOCS3 are functionally linked to each other. They influence signal transduction through the JAK/STAT as well as the MAPK pathway.

The presented model has been analyzed for perturbations in the initial concentration of proteins and phosphatases in the cells. The model was found to be robust with respect to signal response for variations in the initial conditions.

References:

(1) Fischer, P.; Lehmann, U.; Sobota, R.M.; Schmitz, J.; Niemand, C.; Linnemann, S.; Haan, S.; Behrmann, I.; Yoshimura, A.; Johnston, J.A.; Muller-Newen, G.; Heinrich, P.C. & Schaper, F. (2004) The role of the inhibitors of interleukin-6 signal transduction SHP2 and SOCS3 for desensitization of interleukin-6 signaling. Biochemical Journal, 378, 449-460.

(2) Heinrich, P.C.; Behrmann, I.; Muller-Newen, G.; Schaper, F. & Graeve, L. (1998) Interleukin-6-type cytokine signaling through the gp130/JAK/STAT pathway. Biochemical Journal, 334, 297-314.

(3) Heinrich, P.C.; Behrmann, I.; Haan, S.; Hermanns, H.M.; Muller-Newen, G. & Schaper, F. (2003) Principles of interleukin (IL)-6-type cytokine signaling and its regulation. Biochemical Journal, 374, 1-20.

(4) Kim, H. & Baumann, H. (1999) Dual signaling role of the protein tyrosine phosphate SHP-2 in regulating expression of acute-phase plasma proteins by interleukin-6 cytokine receptors in hepatic cells. Molecular and Cellular Biology, 19, 5326-5338.

(5) Schaper, F.; Gendo, C.; Monika, E.; Schmitz, J.; Grimm, C.; Anhuf, D. & Kerr, I.M. (1998) Activation of the protein tyrosine phosphate SHP2 via the interleukin-6 signal transducing receptor protein gp130 requires tyrosine kinase JAK1 and limits acute-phase protein expression. Biochemical Journal, 335, 557-565.