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

Processes

Zhaobin Xu²  Jens O. M. Karlsson¹  Zuyi Huang² 

[1] Department of Mechanical Engineering, Villanova University, Villanova, PA 19085, USA; E-Mail:;Department of Chemical Engineering, Villanova University, Villanova, PA 19085, USA; E-Mail:

关键词: systems engineering;    cellular biology and engineering;    kinetics;    mathematical modeling;    parameter estimation;    sensitivity analysis;   

DOI  :  10.3390/pr3010050

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2015 by the authors; licensee MDPI, Basel, Switzerland.