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The cholesterol biosynthesis pathway regulates IL-10 expression in human Th1 cells

Author

Listed:
  • Esperanza Perucha

    (King’s College London
    King’s College London)

  • Rossella Melchiotti

    (Guy’s and St Thomas’ NHS Foundation Trust and King’s College London)

  • Jack A Bibby

    (King’s College London
    King’s College London)

  • Wing Wu

    (King’s College London
    King’s College London)

  • Klaus Stensgaard Frederiksen

    (Novo Nordisk A/S)

  • Ceri A. Roberts

    (King’s College London
    NHS Blood and Transplant)

  • Zoe Hall

    (University of Cambridge)

  • Gaelle LeFriec

    (King’s College London)

  • Kevin A. Robertson

    (University of Edinburgh)

  • Paul Lavender

    (King’s College London)

  • Jens Gammeltoft Gerwien

    (Novo Nordisk A/S
    Eli Lilly)

  • Leonie S. Taams

    (King’s College London)

  • Julian L. Griffin

    (University of Cambridge)

  • Emanuele Rinaldis

    (Guy’s and St Thomas’ NHS Foundation Trust and King’s College London)

  • Lisa G. M. Baarsen

    (University of Amsterdam
    University of Amsterdam)

  • Claudia Kemper

    (King’s College London
    National Institutes of Health (NIH)
    University of Lübeck)

  • Peter Ghazal

    (University of Edinburgh
    University of Cardiff)

  • Andrew P. Cope

    (King’s College London
    King’s College London)

Abstract

The mechanisms controlling CD4+ T cell switching from an effector to an anti-inflammatory (IL-10+) phenotype play an important role in the persistence of chronic inflammatory diseases. Here, we identify the cholesterol biosynthesis pathway as a key regulator of this process. Pathway analysis of cultured cytokine-producing human T cells reveals a significant association between IL-10 and cholesterol metabolism gene expression. Inhibition of the cholesterol biosynthesis pathway with atorvastatin or 25-hydroxycholesterol during switching from IFNγ+ to IL-10+ shows a specific block in immune resolution, defined as a significant decrease in IL-10 expression. Mechanistically, the master transcriptional regulator of IL10 in T cells, c-Maf, is significantly decreased by physiological levels of 25-hydroxycholesterol. Strikingly, progression to rheumatoid arthritis is associated with altered expression of cholesterol biosynthesis genes in synovial biopsies of predisposed individuals. Our data reveal a link between sterol metabolism and the regulation of the anti-inflammatory response in human CD4+ T cells.

Suggested Citation

  • Esperanza Perucha & Rossella Melchiotti & Jack A Bibby & Wing Wu & Klaus Stensgaard Frederiksen & Ceri A. Roberts & Zoe Hall & Gaelle LeFriec & Kevin A. Robertson & Paul Lavender & Jens Gammeltoft Ger, 2019. "The cholesterol biosynthesis pathway regulates IL-10 expression in human Th1 cells," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-08332-9
    DOI: 10.1038/s41467-019-08332-9
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