Modeling regulatory mechanisms in IL‐6 signal transduction in hepatocytes

Abstract

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) and 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-SHP-2 (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 SHP-2 and SOCS3 influence signaling through the JAK/STAT and the MAPK pathways. It is shown that SHP-2 and SOCS3 do not just regulate the pathway that they are known to be associated with, (SHP-2 with MAPK and SOCS3 with JAK/STAT), but also have a strong effect on the other pathway. Several simulations with SOCS3, SHP-2, and PP2 knockout cells, that is, 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.

Optimal Experimental Design for Parameter Estimation of an IL-6 Signaling Model

“…The FIM is computed from the sensitivity coefficients of the model, which can be an ODE model as shown in Equation (1). Local sensitivity coefficients are defined as…”

“…Interleukin-6 (IL-6) is a cytokine involved in a variety of inflammatory processes [1][2][3][4]. Understanding the signaling pathways associated with extracellular IL-6 excitation is important for elucidating and modulating the biological response to inflammation.…”

“…An IL-6 signaling model (Appendix A) was previously developed in [1][2][3][4]. Originally, a detailed model containing 77 ordinary differential equations (ODEs) and 128 parameters was derived, followed by a model simplification procedure to decrease the number of ODEs and parameters to 13 and 19, respectively.…”

Analysis of IL6 Signal Transduction Model using Reduced Rank Regression

“…The parameters, p, represent the reaction constants, the states, x, are the concentrations of the proteins in the pathway and the input, u, is the stimulating concentration of IL6. A detailed description of the model can be found in [1].…”

“…Although considerable progress in the identification of the molecular components involved in cell functions has been made over the past decades, the underpinning molecular mechanisms remain largely unknown and poorly understood. This paper analyzes an available model of signal transduction pathways in hepatic cells when stimulated by interleukin-6 (IL6) [1]. From the associated medical literature it is known that IL6 represents one of the principal factors involved in the regulation of most Acute Phase Proteins [2].…”