Demystifying the cytokine network: Mathematical models point the way

Abstract

Cytokines provide the means by which immune cells communicate with each other and with parenchymal cells. There are over one hundred cytokines and many exist in families that share receptor components and signal transduction pathways, creating complex networks. Reductionist approaches to understanding the role of specific cytokines, through the use of gene-targeted mice, have revealed further complexity in the form of redundancy and pleiotropy in cytokine function. Creating an understanding of the complex interactions between cytokines and their target cells is challenging experimentally. Mathematical and computational modeling provides a robust set of tools by which complex interactions between cytokines can be studied and analyzed, in the process creating novel insights that can be further tested experimentally. This review will discuss and provide examples of the different modeling approaches that have been used to increase our understanding of cytokine networks. This includes discussion of knowledge-based and data-driven modeling approaches and the recent advance in single-cell analysis. The use of modeling to optimize cytokine-based therapies will also be discussed.

A Modeling Framework to Characterize Cytokine Release upon T‐Cell–Engaging Bispecific Antibody Treatment: Methodology and Opportunities

“…For example, the anti‐inflammatory cytokine IL‐10 plays important roles in the negative regulation of cytokines. Although the dynamic interactions between cytokines are very complex and not completely understood, mechanistic cytokine models are available in the literature and relevant model components may be adapted to this current framework.…”

Network Topology Dynamics of Circulating Biomarkers and Cognitive Performance in Older Cytomegalovirus-seropositive or -seronegative Men and Women

“…There is a growing body of evidence supporting the notion that the immune system is not hermetically self-regulated but functions in intimate interrelations with other physiological systems, including the nervous system (5,37). These interactions are present at the various levels of organization -at the local, as well as at the whole organism level -by sharing a common language of a wide range of cytokines, receptor molecules, hormones, neuropeptides, metabolic and neurotrophic factors allowing crosscommunication (38,39). Particularly in the process of aging, this reciprocal cross-talk may under certain circumstances permit augmentation of maladaptive inflammatory loops, which could disturb homeostasis and contribute to the age-related functional alterations or even to pathological conditions (2,40,41).…”

Human spermatozoa of male patients with subfertility express the interleukin‐6 receptor

“…Nonetheless, although significant the average decrease in sperm motility in response to IL‐6 was only marginal so that it appears reasonable to doubt clinical relevance. This phenomenon could result from the singular IL‐6 stimulation of spermatozoa as cytokines mostly interact in a network with each other (Morel, Lee, & Faeder, ).…”