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

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  • Esperanza Perucha (Lead Author)
  • Rossella Melchiotti
  • Jack A. Bibby
  • Wing Wu
  • Klaus Stensgaard Frederiksen
  • Ceri A Roberts
  • Zoe Hall
  • Gaelle LeFriec
  • Kevin Robertson
  • Jens Gammeltoft Gerwien
  • L. S. Taams
  • Julian L. Griffin
  • Emanuele de Rinaldis
  • Lisa GM van Baarsen
  • Claudia Kemper
  • Peter Ghazal
  • Andrew P Cope

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Original languageEnglish
Article number498
JournalNature Communications
Volume10
DOIs
Publication statusPublished - 30 Jan 2019

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.

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