Paracha Rehan Zafar, Ahmad Jamil, Ali Amjad, Hussain Riaz, Niazi Umar, Tareen Samar Hayat Khan, Aslam Babar
Atta-Ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Islamabad, Pakistan.
Research Center for Modeling and Simulation (RCMS), National University of Sciences and Technology (NUST), Islamabad, Pakistan.
PLoS One. 2014 Sep 25;9(9):e108466. doi: 10.1371/journal.pone.0108466. eCollection 2014.
Sepsis is one of the major causes of human morbidity and results in a considerable number of deaths each year. Lipopolysaccharide-induced sepsis has been associated with TLR4 signalling pathway which in collaboration with the JAK/STAT signalling regulate endotoxemia and inflammation. However, during sepsis our immune system cannot maintain a balance of cytokine levels and results in multiple organ damage and eventual death. Different opinions have been made in previous studies about the expression patterns and the role of proinflammatory cytokines in sepsis that attracted our attention towards qualitative properties of TLR4 and JAK/STAT signalling pathways using computer-aided studies. René Thomas' formalism was used to model septic and non-septic dynamics of TLR4 and JAK/STAT signalling. Comparisons among dynamics were made by intervening or removing the specific interactions among entities. Among our predictions, recurrent induction of proinflammatory cytokines with subsequent downregulation was found as the basic characteristic of septic model. This characteristic was found in agreement with previous experimental studies, which implicate that inflammation is followed by immunomodulation in septic patients. Moreover, intervention in downregulation of proinflammatory cytokines by SOCS-1 was found desirable to boost the immune responses. On the other hand, interventions either in TLR4 or transcriptional elements such as NFκB and STAT were found effective in the downregulation of immune responses. Whereas, IFN-β and SOCS-1 mediated downregulation at different levels of signalling were found to be associated with variations in the levels of proinflammatory cytokines. However, these predictions need to be further validated using wet laboratory experimental studies to further explore the roles of inhibitors such as SOCS-1 and IFN-β, which may alter the levels of proinflammatory cytokines at different stages of sepsis.
脓毒症是人类发病的主要原因之一，每年导致大量死亡。脂多糖诱导的脓毒症与TLR4信号通路有关，该通路与JAK/STAT信号通路协同调节内毒素血症和炎症。然而，在脓毒症期间，我们的免疫系统无法维持细胞因子水平的平衡，导致多器官损伤并最终死亡。先前的研究对脓毒症中促炎细胞因子的表达模式和作用存在不同观点，这促使我们通过计算机辅助研究关注TLR4和JAK/STAT信号通路的定性特性。使用勒内·托马斯的形式主义对TLR4和JAK/STAT信号的脓毒症和非脓毒症动态进行建模。通过干预或去除实体之间的特定相互作用来进行动态比较。在我们的预测中，发现促炎细胞因子的反复诱导及随后的下调是脓毒症模型的基本特征。这一特征与先前的实验研究一致，表明脓毒症患者炎症后会发生免疫调节。此外，发现通过SOCS-1干预促炎细胞因子的下调有利于增强免疫反应。另一方面，发现对TLR4或转录元件如NFκB和STAT的干预在下调免疫反应方面有效。而IFN-β和SOCS-1在不同信号水平介导的下调与促炎细胞因子水平的变化有关。然而，这些预测需要使用湿实验室实验研究进一步验证，以进一步探索SOCS-1和IFN-β等抑制剂的作用，这些抑制剂可能会在脓毒症的不同阶段改变促炎细胞因子的水平。
