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- Title
The cholesterol biosynthesis pathway regulates IL-10 expression in human Th1 cells.
- Authors
Perucha, Esperanza; Melchiotti, Rossella; Bibby, Jack A; Wu, Wing; Frederiksen, Klaus Stensgaard; Roberts, Ceri A.; Hall, Zoe; LeFriec, Gaelle; Robertson, Kevin A.; Lavender, Paul; Gerwien, Jens Gammeltoft; Taams, Leonie S.; Griffin, Julian L.; de Rinaldis, Emanuele; van Baarsen, Lisa G. M.; Kemper, Claudia; Ghazal, Peter; Cope, Andrew P.
- 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. Metabolic pathways are increasingly recognized as crucial determinants of T cell function. Here the authors show that the balance between IFNγ and IL-10 production in human CD4 T cells is modulated by the cholesterol biosynthetic pathway.
- Publication
Nature Communications, 2019, Vol 10, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-019-08332-9