ArticleBMC systems biology2013
Transient oscillatory dynamics of interferon beta signaling in macrophages.
Article in BMC systems biology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed, 23 citations in OpenAlex.
- Transient frequency preference responses in cell signaling systems.NPJ systems biology and applications · 2024Article
- Post-transcriptional regulatory feedback encodes JAK-STAT signal memory of interferon stimulation.Frontiers in immunology · 2022Article
- IFN-β mediates the anti-osteoclastic effect of bisphosphonates and dexamethasone.Frontiers in pharmacology · 2022Article
- Prediction of combination therapies based on topological modeling of the immune signaling network in multiple sclerosis.Genome medicine · 2021Article
- Agent-based modeling and bifurcation analysis reveal mechanisms of macrophage polarization and phenotype pattern distribution.Scientific reports · 2019Article
- A graphical and computational modeling platform for biological pathways.Nature protocols · 2018Article
- IFN-β Plays Both Pro- and Anti-inflammatory Roles in the Rat Cardiac Fibroblast Through Differential STAT Protein Activation.Frontiers in pharmacology · 2018Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundInterferon-beta (IFN-beta) activates the immune response through the type I IFN signaling pathway. IFN-beta is important in the response to pathogen infections and is used as a therapy for Multiple Sclerosis. The mechanisms of self-regulation and control of this pathway allow precise and environment-dependent response of the cells in different conditions. Here we analyzed type I IFN signaling in response to IFN-beta in the macrophage cell line RAW 264.7 by RT-PCR, ELISA and xMAP assays. The experimental results were interpreted by means of a theoretical model of the pathway.
resultsPhosphorylation of the STAT1 protein (pSTAT1) and mRNA levels of the pSTAT1 inhibitor SOCS1 displayed an attenuated oscillatory behavior after IFN-beta activation. In turn, mRNA levels of the interferon regulatory factor IRF1 grew rapidly in the first 50-90 minutes after stimulation until a maximum value, and started to decrease slowly around 200-250 min. The analysis of our kinetic model identified a significant role of the negative feedback from SOCS1 in driving the observed damped oscillatory dynamics, and of the positive feedback from IRF1 in increasing STAT1 basal levels. Our study shows that the system works as a biological damped relaxation oscillator based on a phosphorylation-dephosphorylation network centered on STAT1. Moreover, a bifurcation analysis identified translocation of pSTAT1 dimers to the nucleus as a critical step for regulating the dynamics of type I IFN pathway in the first steps, which may be important in defining the response to IFN-beta therapy.
conclusionsThe immunomodulatory effect of IFN-beta signaling in macrophages takes the form of transient oscillatory dynamics of the JAK-STAT pathway, whose specific relaxation properties determine the lifetime of the cellular response to the cytokine.
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