Investigation of IL-6 and IL-10 Signaling via Mathematical Modeling

Steatosis, i.e., the accumulation of fat in hepatocytes, plays an important role in the progression of non-alcoholic fatty liver disease (NAFLD). It has been shown that STAT3 activation is involved in a decrease of lipid accumulation while C/EBPb is correlated with an increase of fat content and steatosis. Since both these transcription factors can be activated by IL-6 and the pathways leading to their activation are inter-connected, the relative activation levels of these transcription factors are likely to be important in steatosis. Furthermore, it is known that cross-talk exists between IL-6 and IL-10 signaling as both cytokines signal through the Jak-STAT pathway.

This paper develops a model for IL-6 and IL-10 signal transduction and then investigates the effect that stimulation with these cytokines has on the transcription factor dynamics. In an initial step, some parameters of a previously developed IL-6 signaling model are re-estimated based upon newly developed experimental data for the Jak-STAT pathway. Furthermore, the Erk-C/EBPb pathway is extended in the model to also include the dynamics of the activated transcription factor C/EBPb in the nucleus. Since IL-10 signals through the Jak-STAT but not the Erk-C/EBPb pathway, a model for its signal transduction was developed which includes interactions between IL-6 and IL-10 signaling as both mechanisms share signal transduction though the Jak-STAT pathway. Based upon the developed models, the ratio of the activity of Jak-STAT and Erk-C/EBPb was investigated for different stimulation levels of IL-6 and IL-10. These results will be used for the design of future in vitro experiments.