Modeling Regulatory Mechanisms in IL-6 Signal Transduction in Hepatocytes

Cytokines like interleukin-6 (IL-6) play an important role in triggering the acute phase response of the body to injury or inflammation. Signaling by IL-6 involves two pathways: Janus-associated kinases (JAK) & signal transducers and activators of transcription (STAT 3) are activated in the first pathway while the second pathway involves the activation of mitogen-activated protein kinases (MAPK). While it is recognized that both pathways play a major role in IL-6 signal transduction, a majority of studies have focused on signaling through either one of the pathways. However, simultaneous signaling through both JAK/STAT and MAPK pathways is still poorly understood.

In this work, a mathematical model has been developed that integrates signaling through both the JAK/STAT and the MAPK pathway. The presented model is used to analyze the effect of three molecules that are involved in the regulation of IL-6 signaling - SHP2 (domain containing tyrosine phosphatase 2), SOCS3 (suppressor of cytokine signaling 3), and a STAT3 nuclear phosphatase (PP2) - on the dynamics of IL-6 signal transduction in hepatocytes. The obtained results suggest that interactions between SHP2 and SOCS3 influence signaling through the JAK/STAT and the MAPK pathways. It is shown that SHP2 and SOCS3 do not just regulate the pathway that they are known to be associated with, (SHP2 with MAPK and SOCS3 with JAK/STAT), but also have a strong effect on the other pathway. Several simulations with SOCS3, SHP2, and PP2 knockout cells, i.e. where the signaling pathway is unable to produce these proteins, have been performed to characterize the effect of these regulatory proteins on IL-6 signal transduction in hepatocytes.