Rateitschak Katja, Karger Anna, Fitzner Brit, Lange Falko, Wolkenhauer Olaf, Jaster Robert
Systems Biology and Bioinformatics Group, University of Rostock, 18051 Rostock, Germany.
Cell Signal. 2010 Jan;22(1):97-105. doi: 10.1016/j.cellsig.2009.09.019. Epub 2009 Sep 23.
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.
信号转导子和转录激活子（STAT）1主要参与胰腺星状细胞（PSC）中抗纤维化干扰素-γ（IFNγ）效应的介导。在此，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通路的激活情况。在IFNγ饱和浓度下，观察到STAT1激活的三相模式。最初是磷酸化STAT1的快速诱导，随后是平台期，接着是另一个持续时间较长的进一步增加阶段。尽管反馈抑制剂（SOCS1）表达增强，但后期仍出现增加，这与总STAT1蛋白水平的升高相对应。如果以非饱和浓度应用IFNγ，磷酸化STAT1和SOCS1水平在12小时内达到峰值并再次下降，而STAT1蛋白水平仍保持较高。基于常微分方程系统的数学模型将网络组件的时间变化描述为相互作用和转运过程的函数。该模型重现了实验分析的STAT1通路所有组件的激活情况。此外，它在其他实验研究中成功预测了网络组件的动态变化。基于实验结果和建模所得结果，我们认为所应用的IFNγ耗尽以及酪氨酸磷酸酶导致的STAT1去磷酸化是PSC中STAT1激活的限制因素。相比之下，在我们的实验系统中，我们没有获得令人信服的证据表明SOCS1作为一种有效的反馈抑制剂发挥作用。我们相信对STAT1通路数学建模的进一步研究将增进对抗纤维化干扰素作用的理解。
