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首页> 外文期刊>Cellular Signalling >Mathematical modelling of interferon-gamma signalling in pancreatic stellate cells reflects and predicts the dynamics of STAT1 pathway activity
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Mathematical modelling of interferon-gamma signalling in pancreatic stellate cells reflects and predicts the dynamics of STAT1 pathway activity

机译：胰腺星状细胞中干扰素-γ信号传导的数学模型反映并预测STAT1途径活性的动态

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摘要

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.
机译：信号转导子和转录激活子（STAT）1基本上参与了胰腺星状细胞（PSC）中抗纤维化干扰素-γ（IFN gamma）效应的介导。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途径的激活。在IFNγ的饱和浓度下，观察到STAT1激活的三相模式。磷酸STAT1的初始快速诱导后是平稳期，另一个是持续增加的长期阶段。尽管反馈抑制剂（SOCS1）的表达增强，但发生后期增加，并与STAT1总蛋白水平升高相对应。如果以非饱和浓度施用IFNγ，磷酸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。基于常微分方程系统的数学模型描述了网络组件随交互作用和传输过程而变化的时间。该模型再现了通过实验分析的STAT1途径所有成分的激活概况。此外，它还在其他实验研究中成功预测了网络组件的动态。基于实验结果和建模结果，我们建议应用酪氨酸磷酸酶耗尽IFNγ和STAT1去磷酸化作为PSC中STAT1激活的限制因素。相比之下，我们没有获得令人信服的证据证明SOCS1在我们的实验系统中充当有效的反馈抑制剂。我们相信，进一步研究STAT1途径的数学模型将增进对抗纤维化干扰素作用的了解。

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