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 α; TNF-α) and anti-inflammatory (interleukin-10; IL-10) cytokines on the activation of the transcription factor nuclear factor κB (NF-κB) under continuous lipopolysaccharide (LPS) stimulation (mimicking bacterial infection). In the model, IL-10 upregulates its own production (positive feedback) and also downregulates TNF-α production through NF-κB (negative feedback). In addition, TNF-α upregulates its own production through NF-κB (positive feedback). Eight model parameters are selected for estimation involving sensitivity analysis and clustering techniques. We validate the mathematical model predictions by measuring phosphorylated OPEN ACCESSProcesses 2015, 3 2 NF-κB, de novo synthesized TNF-α and IL-10 in RAW 264.7 macrophages exposed to LPS. This integrated model represents a first step towards modeling the interaction between proand anti-inflammatory signaling.
The microbiota is a vast community of microbial cells living in symbiosis with the host. The intestinal microbiota stands out due to its direct link with overall host health. The molecular complexity of the microbiota suggests broad activation of multiple pattern recognition receptors on intestinal epithelial cells and dendritic cells. Indeed, mutations in pattern recognition receptors are correlated with increased inflammatory bowel disease incidence. Clearly, the interaction between microbiota and host cells is integral to a healthy host, but what regulates this interaction is poorly understood. In our previous work we reported that indole, a tryptophan metabolite present in the GI tract and strictly produced by the microbiota (not host cells), downregulates NFκB activation and inflammation in intestinal epithelial cells. We hypothesize that indole limits inflammation by modulating pattern recognition receptor-mediated activation of dendritic cells, key sentinels of gut homeostasis. Here, we demonstrate that dendritic cells conditioned with indole at physiologic concentrations have decreased production of pro-inflammatory cytokines after differential pattern recognition receptor stimulation. Notably, indole decreases the severity of DSS-induced colitis. This suggests an anti-inflammatory role for indole in maintenance of homeostasis in the GI tract and reveals a new therapeutic strategy for the treatment of inflammatory bowel disease.
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