Mathematical modelling of interferon-γ signalling in pancreatic stellate cells reflects and predicts the dynamics of STAT1 pathway activity
Mathematical modelling of interferon-γ signalling in pancreatic stellate cells reflects and predicts the dynamics of STAT1 pathway activity
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DOI：
10.1016/j.cellsig.2009.09.019
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发表时间：
2010-01-01
影响因子：
4.8
通讯作者：
Jaster, Robert
中科院分区：
文献类型：
--
作者：
Rateitschak, Katja;Karger, Anna;Jaster, Robert
信号转导和转录激活因子(STAT)1主要参与介导胰腺星状细胞(PSC)的抗纤维化干扰素-γ(IFN-γ)效应。在这里，我们通过将定量数据生成与数学建模相结合，进一步分析了PSC系中STAT1通路的激活。在饱和浓度的干扰素-γ作用下，观察到STAT1的激活呈三相模式。最初，快速诱导磷酸化STAT1之后是一个平台期和另一个持续时间较长的进一步增加阶段。尽管反馈抑制物(SOCS1)的表达增强，但后期的增加发生了，并与总STAT1蛋白水平的增加相对应。如果在非饱和浓度下应用干扰素-γ，则磷酸化STAT1和SOCS1水平在12小时内达到峰值并再次下降，而STAT1蛋白水平仍然很高。该数学模型基于一组常微分方程组，描述了作为相互作用和传输过程的函数的网络组件的时间变化。该模型再现了经过实验分析的STAT1通路所有组件的激活曲线。此外，在更多的实验研究中，它成功地预测了网络组件的动力学。根据实验结果和模拟结果，我们认为应用干扰素-γ和酪氨酸磷酸酶使STAT1去磷酸化是PSC中STAT1激活的限制因素。相反，我们没有得到令人信服的证据表明SOCS1在我们的实验系统中起到了有效的反馈抑制作用。我们相信，对STAT1通路的数学建模的进一步研究将提高对抗纤维化干扰素作用的理解。(C)2009 Elsevier Inc.保留所有权利。
Signal transducer and activator of transcription (STAT) 1 is essentially involved in the mediation of antifibrotic interferon-gamma (IFN gamma) effects in pancreatic stellate cells (PSC). Here, we have further analysed the activation of the STAT1 pathway in a PSC line by combining quantitative data generation with mathematical modelling. At saturating concentrations of IFN gamma, a triphasic pattern of STAT1 activation was observed. An initial, rapid induction of phospho-STAT1 was followed by a plateau phase and another, long-lasting phase of further increase. The late increase occurred despite enhanced expression of the feedback inhibitor (SOCS1), and corresponded to increased levels of total STAT1 protein. If IFN gamma was applied at non-saturating concentrations, phospho-STAT1 and SOCS1 levels peaked and declined again over a 12 hour period, while STAT1 protein levels remained high. The mathematical model, based on a system of ordinary differential equations, describes temporal changes of the network components as a function of interactions and transport processes. The model reproduced activation profiles of all components of the STAT1 pathway that were experimentally analysed. Furthermore, it successfully predicted the dynamics of network components in additional experimental studies. Based on experimental findings and the results obtained from modelling, we suggest exhaustion of applied IFN gamma and STAT1 dephosphorylation by tyrosine phosphatases as limiting factors of STAT1 activation in PSC. In contrast, we did not obtain compelling evidence that SOCS1 acts as an efficient feedback inhibitor in our experimental system We believe that further investigations into mathematical modelling of the STAT1 pathway will improve the understanding of the antifibrotic interferon action. (C) 2009 Elsevier Inc. All rights reserved.