Investigation of IL-6 and IL-10 signalling via mathematical modelling.

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∕EBP is correlated with an increase of fat content and steatosis. It is known that STAT3 and C∕EBP are activated by IL-6 and that IL-6 signalling is also affected by IL-10, even though the exact mechanism is unclear. 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 signalling model are re-estimated based upon newly developed experimental data for the Jak-STAT pathway. Furthermore, the Erk-C∕EBP pathway model is extended to also include the activated transcription factor C∕EBP in the nucleus. Since IL-10 signals through the Jak-STAT but not the Erk-C∕EBP pathway, a model was developed which includes interaction between IL-6 and IL-10 signalling as both mechanisms share signal transduction through the Jak-STAT pathway. Based upon the model, the activity ratio of Jak-STAT and Erk-C∕EBP was investigated for different stimulation levels of IL-6 and IL-10.