1. Computational and Systems Biology
  2. Immunology and Inflammation
Download icon

Competitive binding of STATs to receptor phospho-Tyr motifs accounts for altered cytokine responses

  1. Stephan Wilmes
  2. Polly-Anne Jeffrey
  3. Jonathan Martinez-Fabregas
  4. Maximillian Hafer
  5. Paul K Fyfe
  6. Elizabeth Pohler
  7. Silvia Gaggero
  8. Martin Lopez-Garcia
  9. Grant Lythe
  10. Charles Taylor
  11. Thomas Guerrier
  12. David Launay
  13. Suman Mitra
  14. Jacob Piehler
  15. Carmen Molina-Paris  Is a corresponding author
  16. Ignacio Moraga Gonzalez  Is a corresponding author
  1. University of Dundee, United Kingdom
  2. University of Leeds, United Kingdom
  3. University of Osnabrück, Germany
  4. Université de Lille, France
  5. Universität Osnabrück, Germany
Research Article
  • Cited 0
  • Views 1,186
  • Annotations
Cite this article as: eLife 2021;10:e66014 doi: 10.7554/eLife.66014

Abstract

Cytokines elicit pleiotropic and non-redundant activities despite strong overlap in their usage of receptors, JAKs and STATs molecules. We use IL-6 and IL-27 to ask how two cytokines activating the same signaling pathway have different biological roles. We found that IL-27 induces more sustained STAT1 phosphorylation than IL-6, with the two cytokines inducing comparable levels of STAT3 phosphorylation. Mathematical and statistical modelling of IL-6 and IL-27 signaling identified STAT3 binding to GP130, and STAT1 binding to IL-27Rα, as the main dynamical processes contributing to sustained pSTAT1 levels by IL-27. Mutation of Tyr613 on IL-27Rα decreased IL-27-induced STAT1 phosphorylation by 80% but had limited effect on STAT3 phosphorylation. Strong receptor/STAT coupling by IL-27 initiated a unique gene expression program, which required sustained STAT1 phosphorylation and IRF1 expression and was enriched in classical Interferon Stimulated Genes. Interestingly, the STAT/receptor coupling exhibited by IL-6/IL-27 was altered in patients with systemic lupus erythematosus (SLE). IL-6/IL-27 induced a more potent STAT1 activation in SLE patients than in healthy controls, which correlated with higher STAT1 expression in these patients. Partial inhibition of JAK activation by sub-saturating doses of Tofacitinib specifically lowered the levels of STAT1 activation by IL-6. Our data show that receptor and STATs concentrations critically contribute to shape cytokine responses and generate functional pleiotropy in health and disease.

Data availability

Python (version 3.7) codes for the ABC-SMC model selection and parameter inference can be found in the public repository "https://github.com/PollyJeffrey/Cytokine_modelling", along with the results of the analysis. Phospho-proteomic and proteomic datasets were uploaded to the Proteome Exchange platform with accession numbers PXD024657 and PXD024188 respectively. RNA-seq dataset was uploaded in the GSE database with accession number GSE164479.

The following data sets were generated

Article and author information

Author details

  1. Stephan Wilmes

    Division of Cell Signaling and Immunology, School of Life Sciences, University of Dundee, Dundee, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4112-710X
  2. Polly-Anne Jeffrey

    Department of Applied Mathematics, University of Leeds, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6476-0402
  3. Jonathan Martinez-Fabregas

    Division of Cell Signaling and Immunology, School of Life Sciences, University of Dundee, Dundee, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5809-065X
  4. Maximillian Hafer

    Department of Biology, University of Osnabrück, Osnabrück, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0853-2637
  5. Paul K Fyfe

    Division of Cell Signaling and Immunology, School of Life Sciences, University of Dundee, Dundee, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3541-2294
  6. Elizabeth Pohler

    Division of Cell Signaling and Immunology, School of Life Sciences, University of Dundee, Dundee, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Silvia Gaggero

    CANTHER and Institut pour la Recherche sur le Cancer de Lille, Université de Lille, Lille, France
    Competing interests
    The authors declare that no competing interests exist.
  8. Martin Lopez-Garcia

    Department of Applied Mathematics, University of Leeds, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. Grant Lythe

    Department of Applied Mathematics, University of Leeds, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  10. Charles Taylor

    Department of Applied Mathematics, University of Leeds, Leeds, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  11. Thomas Guerrier

    INFINITE - Institute for Translational Research in Inflammation, Université de Lille, Lille, France
    Competing interests
    The authors declare that no competing interests exist.
  12. David Launay

    INFINITE - Institute for Translational Research in Inflammation, Université de Lille, Lille, France
    Competing interests
    The authors declare that no competing interests exist.
  13. Suman Mitra

    CANTHER and Institut pour la Recherche sur le Cancer de Lille, Université de Lille, Lille, France
    Competing interests
    The authors declare that no competing interests exist.
  14. Jacob Piehler

    Department of Biology/Chemistry, Universität Osnabrück, Osnabrück, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2143-2270
  15. Carmen Molina-Paris

    Department of Applied Mathematics, University of Leeds, Leeds, United Kingdom
    For correspondence
    C.MolinaParis@leeds.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
  16. Ignacio Moraga Gonzalez

    Division of Cell Signaling and Immunology, School of Life Sciences, University of Dundee, Dundee, United Kingdom
    For correspondence
    imoragagonzalez@dundee.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9909-0701

Funding

Horizon 2020 Framework programme (714680)

  • Stephan Wilmes
  • Jonathan Martinez-Fabregas
  • Paul K Fyfe
  • Ignacio Moraga Gonzalez

Wellcome Trust (202323/Z/16/Z)

  • Stephan Wilmes
  • Ignacio Moraga Gonzalez

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: This study was authorized by the French Competent Authority dealing with Research on Human Biological Samples namely the French Ministry of Research. The Authorization number is ECH 19/04. all patients gave their written informed consent

Reviewing Editor

  1. Frederik Graw, Heidelberg University, Germany

Publication history

  1. Received: December 22, 2020
  2. Accepted: April 18, 2021
  3. Accepted Manuscript published: April 19, 2021 (version 1)
  4. Version of Record published: May 5, 2021 (version 2)

Copyright

© 2021, Wilmes et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 1,186
    Page views
  • 206
    Downloads
  • 0
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Computational and Systems Biology
    Michael S Lauer, Deepshikha Roychowdhury
    Research Article Updated

    Previous reports have described worsening inequalities of National Institutes of Health (NIH) funding. We analyzed Research Project Grant data through the end of Fiscal Year 2020, confirming worsening inequalities beginning at the time of the NIH budget doubling (1998–2003), while finding that trends in recent years have reversed for both investigators and institutions, but only to a modest degree. We also find that career-stage trends have stabilized, with equivalent proportions of early-, mid-, and late-career investigators funded from 2017 to 2020. The fraction of women among funded PIs continues to increase, but they are still not at parity. Analyses of funding inequalities show that inequalities for investigators, and to a lesser degree for institutions, have consistently been greater within groups (i.e. within groups by career stage, gender, race, and degree) than between groups.

    1. Computational and Systems Biology
    2. Epidemiology and Global Health
    Hannah R Meredith et al.
    Research Article

    Human mobility is a core component of human behavior and its quantification is critical for understanding its impact on infectious disease transmission, traffic forecasting, access to resources and care, intervention strategies, and migratory flows. When mobility data are limited, spatial interaction models have been widely used to estimate human travel, but have not been extensively validated in low- and middle-income settings. Geographic, sociodemographic, and infrastructure differences may impact the ability for models to capture these patterns, particularly in rural settings. Here, we analyzed mobility patterns inferred from mobile phone data in four Sub-Saharan African countries to investigate the ability for variants on gravity and radiation models to estimate travel. Adjusting the gravity model such that parameters were fit to different trip types, including travel between more or less populated areas and/or different regions, improved model fit in all four countries. This suggests that alternative models may be more useful in these settings and better able to capture the range of mobility patterns observed.