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

Perucha, Esperanza, Melchiotti, Rossella, Bibby, Jack A., Wu, Wing, Stensgaard 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 and Cope, Andrew P. 2019. The cholesterol biosynthesis pathway regulates IL-10 expression in human Th1 cells. Nature Communications 10 , 498. 10.1038/s41467-019-08332-9

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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.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Medicine
Additional Information: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
Publisher: Nature Research
ISSN: 2041-1723
Date of First Compliant Deposit: 7 February 2019
Date of Acceptance: 18 December 2018
Last Modified: 26 May 2020 14:30
URI: http://orca.cf.ac.uk/id/eprint/119292

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