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Qi2013 - IL-6 and IFN crosstalk model


ABSTRACT: Qi2013 - IL-6 and IFN crosstalk model This model [BIOMD0000000544] describes the crosstalk between IFN-gamma and IL-6 induced signalling; it aims to outline mechanisms and factors that may control the interaction between both signalling pathways, discussing a role of heterodimer formation in signalling dysfunction. To account for the possibility of different IFNR and gp130 binding sites for STAT1 and STAT3, model 1 [BIOMD0000000543] assumes that there is no competition between STAT1 and STAT3 for the receptor complexes (includes two extra reactions). The reverse of this is true in model 2 [BIOMD0000000544] where it generally is assumed that there is competition between STAT1 and STAT3 for the receptor complexes. This model is described in the article: Elucidating the crosstalk mechanism between IFN-gamma and IL-6 via mathematical modelling. Qi YF, Huang YX, Wang HY, Zhang Y, Bao YL, Sun LG, Wu Y, Yu CL, Song ZB, Zheng LH, Sun Y, Wang GN, Li YX. BMC Bioinformatics 2013; 14: 41 Abstract: BACKGROUND: Interferon-gamma (IFN-gamma) and interleukin-6 (IL-6) are multifunctional cytokines that regulate immune responses, cell proliferation, and tumour development and progression, which frequently have functionally opposing roles. The cellular responses to both cytokines are activated via the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. During the past 10 years, the crosstalk mechanism between the IFN-gamma and IL-6 pathways has been studied widely and several biological hypotheses have been proposed, but the kinetics and detailed crosstalk mechanism remain unclear. RESULTS: Using established mathematical models and new experimental observations of the crosstalk between the IFN-gamma and IL-6 pathways, we constructed a new crosstalk model that considers three possible crosstalk levels: (1) the competition between STAT1 and STAT3 for common receptor docking sites; (2) the mutual negative regulation between SOCS1 and SOCS3; and (3) the negative regulatory effects of the formation of STAT1/3 heterodimers. A number of simulations were tested to explore the consequences of cross-regulation between the two pathways. The simulation results agreed well with the experimental data, thereby demonstrating the effectiveness and correctness of the model. CONCLUSION: In this study, we developed a crosstalk model of the IFN-gamma and IL-6 pathways to theoretically investigate their cross-regulation mechanism. The simulation experiments showed the importance of the three crosstalk levels between the two pathways. In particular, the unbalanced competition between STAT1 and STAT3 for IFNR and gp130 led to preferential activation of IFN-gamma and IL-6, while at the same time the formation of STAT1/3 heterodimers enhanced preferential signal transduction by sequestering a fraction of the activated STATs. The model provided a good explanation of the experimental observations and provided insights that may inform further research to facilitate a better understanding of the cross-regulation mechanism between the two pathways. This model is hosted on BioModels Database and identified by: BIOMD0000000544. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

SUBMITTER: Vincent Knight-Schrijver  

PROVIDER: BIOMD0000000544 | BioModels | 2014-08-19

REPOSITORIES: BioModels

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Elucidating the crosstalk mechanism between IFN-gamma and IL-6 via mathematical modelling.

Qi Yun-feng YF   Huang Yan-xin YX   Wang Hong-yan HY   Zhang Yu Y   Bao Yong-li YL   Sun Lu-guo LG   Wu Yin Y   Yu Chun-lei CL   Song Zhen-bo ZB   Zheng Li-hua LH   Sun Ying Y   Wang Guan-nan GN   Li Yu-xin YX  

BMC bioinformatics 20130206


BACKGROUND: Interferon-gamma (IFN-gamma) and interleukin-6 (IL-6) are multifunctional cytokines that regulate immune responses, cell proliferation, and tumour development and progression, which frequently have functionally opposing roles. The cellular responses to both cytokines are activated via the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. During the past 10 years, the crosstalk mechanism between the IFN-gamma and IL-6 pathways has been studied widely an  ...[more]

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