Modeling the Dynamics of Acute Phase Protein Expression in Human Hepatoma Cells Stimulated by IL-6

Zhaobin Xu,Jens Karlsson,Zuyi Huang

doi:10.3390/pr3010050

Zhaobin Xu, Jens Karlsson + Show 1 more

Open Access

https://doi.org/10.3390/pr3010050

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Journal: Processes	Publication Date: Jan 14, 2015
Citations: 27	License type: CC BY 4.0

Affiliation: Villanova University

Abstract

Interleukin-6 (IL-6) is a systemic inflammatory mediator that triggers the human body’s acute phase response to trauma or inflammation. Although mathematical models for IL-6 signaling pathways have previously been developed, reactions that describe the expression of acute phase proteins were not included. To address this deficiency, a recent model of IL-6 signaling was extended to predict the dynamics of acute phase protein expression in IL-6-stimulated HepG2 cells (a human hepatoma cell line). This included reactions that describe the regulation of haptoglobin, fibrinogen, and albumin secretion by nuclear transcription factors STAT3 dimer and C/EBPβ. This new extended model was validated against two different sets of experimental data. Using the validated model, a sensitivity analysis was performed to identify seven potential drug targets to regulate the secretion of haptoglobin, fibrinogen, and albumin. The drug-target binding kinetics for these seven targets was then integrated with the IL-6 kinetic model to rank them based upon the influence of their pairing with drugs on acute phase protein dynamics. It was found that gp80, JAK, and gp130 were the three most promising drug targets and that it was possible to reduce the therapeutic dosage by combining drugs aimed at the top three targets in a cocktail. These findings suggest hypotheses for further experimental investigation.

Highlights

Interleukin-6 (IL-6) has been identified as one of the major systemic mediators that orchestrate acute phase response (APR) in the human body, as evidenced by the fact that IL-6 can stimulate the synthesis of most acute phase proteins in liver cells [1]
Adding the signaling pathways associated with these cytokines can provide a more comprehensive model of the acute phase response, it would be a challenging task currently due to the following two reasons: (1) not all the reactions and pathways that connect these cytokines to acute phase proteins are known; (2) limited quantitative data are available for acute phase protein expression in cells stimulated by these cytokines
The extended IL-6 model will serve as a good starting point for incorporating other signaling pathways in the future, if quantitative data become available for acute phase protein expression following stimulation by other cytokines

Summary

Introduction

Interleukin-6 (IL-6) has been identified as one of the major systemic mediators that orchestrate acute phase response (APR) in the human body, as evidenced by the fact that IL-6 can stimulate the synthesis of most acute phase proteins in liver cells [1]. IL-6 translocates to the liver, via the blood stream, where it stimulates hepatocytes and activates a cascade of intracellular signal transduction pathways. This leads to the activation of transcription factors, such as nuclear STAT3 dimer and C/EBPβ. Nuclear STAT3 dimer and C/EBPβ have been identified as the transcription factors involved in these two signaling pathways, respectively [3,4].

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