Formal Modelling of Toll like Receptor 4 and JAK/STAT Signalling Pathways: Insight into the Roles of SOCS-1, Interferon-β and Proinflammatory Cytokines in Sepsis

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.