title: Complex pattern of interleukin-11-induced inflammation revealed by mathematically modeling the dynamics of C-reactive protein.
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.
authors.affiliation: Institute for Medical Biomathematics (IMBM), POB 282, Hate'ena St. 10, 60991, Bene-Ataroth, Israel.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Kheifetz
authors.forename: Moran
authors.initials: M
authors.lastname: Elishmereni
authors.forename: Zvia
authors.initials: Z
authors.lastname: Agur
mesh_terms: D015415:Biomarkers / Q000097:blood; D001943:Breast Neoplasms / Q000097:blood / Q000188:drug therapy; D002097:C-Reactive Protein / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism*; D017370:Interleukin-11 / Q000097:blood / Q000276:immunology* / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D018448:Models, Immunological
chemical_list: D015415:Biomarkers; D017370:Interleukin-11; D002097:C-Reactive Protein