Khatibi Shabnam, Babon Jeff, Wagner John, Manton Jonathan H, Tan Chin Wee, Zhu Hong-Jian, Wormald Sam, Burgess Antony W
a Department of Electrical and Electronic Engineering , University of Melbourne , Parkville , VIC , Australia.
b Structural Biology Division, The Walter and Eliza Hall Institute of Medical Research (WEHI) , Parkville , VIC , Australia.
Growth Factors. 2017 Jun;35(2-3):100-124. doi: 10.1080/08977194.2017.1363746.
Mathematical models for TGF-β and IL-6 signalling have been linked, providing a platform for analyzing the crosstalk between the systems. An integrated IL-6:TGF-β model was developed via a reduced set of reaction equations which incorporate both feedback loops and appropriate time-delays for transcription and translation processes. The model simulates stable, robust and realistic responses to both ligands. Pulsatile (multiple pulses) inputs for both TGF-β and IL-6 have been simulated to investigate the effects of each ligand on the sensitivity, equilibrium and dynamic responses of the integrated signalling system. In our simulations the crosstalk between constant IL-6 and TGF-β signalling via SMAD7 does not appear to be sufficient to render the cells resistant to TGF-β inhibition. However, the simulations predict that pulsatile IL-6 stimulation would increase SMAD7 levels substantially and consequentially, lead to resistance to TGF-β. The model also allows the prediction of the integrated signalling pathway responses to the mutation of key components, e.g. Gp130 .
转化生长因子-β（TGF-β）和白细胞介素-6（IL-6）信号传导的数学模型已相互关联，为分析这两个系统之间的串扰提供了一个平台。通过一组简化的反应方程建立了一个整合的IL-6:TGF-β模型，该方程纳入了反馈回路以及转录和翻译过程的适当时间延迟。该模型模拟了对两种配体的稳定、稳健且现实的反应。已模拟了TGF-β和IL-6的脉冲式（多个脉冲）输入，以研究每种配体对整合信号系统的敏感性、平衡和动态反应的影响。在我们的模拟中，通过SMAD7的恒定IL-6和TGF-β信号传导之间的串扰似乎不足以使细胞对TGF-β抑制产生抗性。然而，模拟预测脉冲式IL-6刺激会大幅提高SMAD7水平，并因此导致对TGF-β的抗性。该模型还能够预测整合信号通路对关键成分（如Gp130）突变的反应。
