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

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 Gerwien, Leonie S. Taams, Julian L. Griffin, Emanuele Rinaldis, Lisa G. M. Baarsen, Claudia Kemper, Peter Ghazal and Andrew P. Cope ()
Additional contact information
Esperanza Perucha: 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
Wing Wu: King’s College London
Klaus Stensgaard Frederiksen: Novo Nordisk A/S
Ceri A. Roberts: King’s College London
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
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
Claudia Kemper: King’s College London
Peter Ghazal: University of Edinburgh
Andrew P. Cope: King’s College London

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-08332-9

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