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Open Access Highly Accessed Research article

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

Yun-feng Qi1, Yan-xin Huang1*, Hong-yan Wang1, Yu Zhang1, Yong-li Bao1, Lu-guo Sun1, Yin Wu1, Chun-lei Yu1, Zhen-bo Song1, Li-hua Zheng1, Ying Sun1, Guan-nan Wang1 and Yu-xin Li2*

Author Affiliations

1 National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, 130024, Changchun, China

2 Research Center of Agriculture and Medicine Gene Engineering of Ministry of Education, Northeast Normal University, 130024, ChangChun, China

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BMC Bioinformatics 2013, 14:41  doi:10.1186/1471-2105-14-41

Published: 6 February 2013

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.