Mathematical Modeling of Pro- and Anti-Inflammatory Signaling in Macrophages

Inflammation is a beneficial mechanism that is usually triggered by injury or infection and is designed to return the body to homeostasis. However, uncontrolled or sustained inflammation can be deleterious and has been shown to be involved in the etiology of several diseases, including inflammatory bowel disorder and asthma. Therefore, effective anti-inflammatory signaling is important in the maintenance of homeostasis in the body. However, the inter-play between pro- and anti-inflammatory signaling is not fully understood. In the present study, we develop a mathematical model to describe integrated pro- and anti-inflammatory signaling in macrophages. The model incorporates the feedback effects of de novo synthesized pro-inflammatory (tumor necrosis factor alpha; TNF-a) and anti-inflammatory (interleukin-10; IL-10) cytokines on the activation of the transcription factor nuclear factor kappaB (NF-kB) under continuous lipopolysaccharide (LPS) stimulation (mimicking bacterial infection). In the model, IL-10 upregulates its own production (positive feedback) and also downregulates TNF-a production through NF-kB (negative feedback). In addition, TNF-a upregulates its own production through NF-kB (positive feedback). Eight model parameters are selected for estimation involving sensitivity analysis and clustering techniques. We validate the mathematical model predictions by measuring phosphorylated NF-kB, de novo synthesized TNF-a and IL-10 in RAW 264.7 macrophages exposed to LPS. This integrated model represents a first step towards modeling the interaction between pro- and anti-inflammatory signaling.