Mathematical Modeling of Pro- and Anti-Inflammatory Signaling in Macrophages
Mathematical Modeling of Pro- and Anti-Inflammatory Signaling in Macrophages
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DOI：
10.3390/pr3010001
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发表时间：
2015-03-01
期刊：
影响因子：
3.5
通讯作者：
Jayaraman, Arul
中科院分区：
文献类型：
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作者：
Maiti, Shreya;Dai, Wei;Jayaraman, Arul
炎症是一种有益的机制，通常由损伤或感染引发，旨在使身体恢复体内平衡。然而，不受控制或持续的炎症可能是有害的，并已被证明与几种疾病的病因有关，包括炎症性肠病和哮喘。因此，有效的抗炎信号在维持体内稳态中很重要。然而，促炎和抗炎信号之间的相互作用尚不完全清楚。在本研究中，我们建立了一个数学模型来描述巨噬细胞中综合的促炎和抗炎信号。该模型结合了新合成的促炎因子（肿瘤坏死因子α； tnf - α）和抗炎因子（白细胞介素-10；IL-10）在持续脂多糖（LPS）刺激（模拟细菌感染）下对转录因子核因子κ B （nf - κ B）激活的反馈效应。在模型中，IL-10上调自身的生成（正反馈），并通过NF-kappa B下调tnf - α的生成（负反馈）。此外，tnf - α通过NF-kappa B（正反馈）上调自身的生成。选取8个模型参数进行敏感性分析和聚类技术估计。我们通过测量暴露于LPS的RAW 264.7巨噬细胞中磷酸化的NF-kappa B、新生合成的tnf - α和IL-10来验证数学模型的预测。这个综合模型代表了模拟促炎和抗炎信号之间相互作用的第一步。
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-alpha) and anti-inflammatory (interleukin-10; IL-10) cytokines on the activation of the transcription factor nuclear factor kappa B (NF-kappa B) under continuous lipopolysaccharide (LPS) stimulation (mimicking bacterial infection). In the model, IL-10 upregulates its own production (positive feedback) and also downregulates TNF-alpha production through NF-kappa B (negative feedback). In addition, TNF-alpha upregulates its own production through NF-kappa B (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-kappa B, de novo synthesized TNF-alpha 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.