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Complex pattern of interleukin-11-induced inflammation revealed by mathematically modeling the dynamics of C-reactive protein

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Abstract

Inflammation underlies many diseases and is an undesired effect of several therapy modalities. Biomathematical modeling can help unravel the complex inflammatory processes and the mechanisms triggering their emergence. We developed a model for induction of C-reactive protein (CRP), a clinically reliable marker of inflammation, by interleukin (IL)-11, an approved cytokine for treatment of chemotherapy-induced thrombocytopenia. Due to paucity of information on the mechanisms underlying inflammation-induced CRP dynamics, our model was developed by systematically evaluating several models for their ability to retrieve variable CRP profiles observed in IL-11-treated breast cancer patients. The preliminary semi-mechanistic models were designed by non-linear mixed-effects modeling, and were evaluated by various performance criteria, which test goodness-of-fit, parsimony and uniqueness. The best-performing model, a robust population model with minimal inter-individual variability, uncovers new aspects of inflammation dynamics. It shows that CRP clearance is a nonlinear self-controlled process, indicating an adaptive anti-inflammatory reaction in humans. The model also reveals a dual IL-11 effect on CRP elevation, whereby the drug has not only a potent immediate influence on CRP incline, but also a long-term influence inducing elevated CRP levels for several months. Consistent with this, model simulations suggest that periodic IL-11 therapy may result in prolonged low-grade (chronic) inflammation post treatment. Future application of the model can therefore help design improved IL-11 regimens with minimized long-term CRP toxicity. Our study illuminates the dynamics of inflammation and its control, and provides a prototype for progressive modeling of complex biological processes in the medical realm and beyond.

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Acknowledgments

The authors thank Dr. Marina Kleiman, Prof. Gerard Wagemaker and Yuri Kogan for helpful discussions. This work was supported by the Chai Foundation.

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The authors declare that they have no conflict of interest.

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  1. Institute for Medical Biomathematics (IMBM), POB 282, Hate’ena St. 10, 60991, Bene-Ataroth, Israel

    Yuri Kheifetz, Moran Elishmereni & Zvia Agur

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  1. Yuri Kheifetz
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  2. Moran Elishmereni
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Correspondence to Zvia Agur.

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Kheifetz, Y., Elishmereni, M. & Agur, Z. Complex pattern of interleukin-11-induced inflammation revealed by mathematically modeling the dynamics of C-reactive protein. J Pharmacokinet Pharmacodyn 41, 479–491 (2014). https://doi.org/10.1007/s10928-014-9383-z

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