Modelling and simulating interleukin-10 production and regulation by macrophages after stimulation with an immunomodulator of parasitic nematodes
Modelling and simulating interleukin-10 production and regulation by macrophages after stimulation with an immunomodulator of parasitic nematodes
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DOI：
10.1111/j.1742-4658.2009.07068.x
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发表时间：
2009-07-01
期刊：
影响因子：
5.4
通讯作者：
Hammerstein, Peter
中科院分区：
文献类型：
--
作者：
Figueiredo, Ana Sofia;Hoefer, Thomas;Hammerstein, Peter
寄生线虫可通过诱导免疫调节细胞因子如白细胞介素-10（IL-10）下调宿主的免疫应答。为了确定潜在的机制，我们在体外测定了巨噬细胞中IL-10的产生，以响应来自Acanthocheilonema viteae的半胱氨酸蛋白酶抑制剂（一种丝虫的免疫调节蛋白），并开发了IL-10调节的数学模型。IL-10的表达需要刺激的促分裂原活化蛋白激酶细胞外信号调节激酶（ERK）和p38，我们建议，负反馈机制，在信号传导水平上发挥作用，是负责瞬时IL-10的生产，可以由一个持续的高原。具体地，通过分泌的IL-10对ERK途径具有负反馈的模型解释了实验数据。因此，该模型预测持续的磷酸化p38动力学，而ERK激活的变化从短暂的持续时，浓度的免疫调节蛋白的刺线虫viteae增加。我们表明，IL-10可以调节其自身的生产自分泌的方式，ERK和p38控制IL-10的幅度，持续时间和稳态。我们还表明，p38通过分泌IL-10（自分泌串扰）影响ERK。这些发现证明了会聚信号传导途径如何差异化地控制IL-10信号的动力学特性。
Parasitic nematodes can downregulate the immune response of their hosts through the induction of immunoregulatory cytokines such as interleukin-10 (IL-10). To define the underlying mechanisms, we measured in vitro the production of IL-10 in macrophages in response to cystatin from Acanthocheilonema viteae, an immunomodulatory protein of filarial nematodes, and developed mathematical models of IL-10 regulation. IL-10 expression requires stimulation of the mitogen-activated protein kinases extracellular signal-regulated kinase (ERK) and p38, and we propose that a negative feedback mechanism, acting at the signalling level, is responsible for transient IL-10 production that can be followed by a sustained plateau. Specifically, a model with negative feedback on the ERK pathway via secreted IL-10 accounts for the experimental data. Accordingly, the model predicts sustained phospho-p38 dynamics, whereas ERK activation changes from transient to sustained when the concentration of immunomodulatory protein of Acanthocheilonema viteae increases. We show that IL-10 can regulate its own production in an autocrine fashion, and that ERK and p38 control IL-10 amplitude, duration and steady state. We also show that p38 affects ERK via secreted IL-10 (autocrine crosstalk). These findings demonstrate how convergent signalling pathways may differentially control kinetic properties of the IL-10 signal.