The cholesterol biosynthesis pathway regulates IL-10 expression in human Th1 cells
File(s)
Author(s)
Type
Journal Article
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 Issued
2019-01-30
Date Acceptance
2018-12-18
Citation
Nature Communications, 2019, 10 (1)
ISSN
2041-1723
Publisher
Nature Research (part of Springer Nature)
Journal / Book Title
Nature Communications
Volume
10
Issue
1
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/30700717
PII: 10.1038/s41467-019-08332-9
Subjects
Atorvastatin
Cholesterol
Humans
Hydroxycholesterols
Interferon-gamma
Interleukin-10
Th1 Cells
Publication Status
Published
Coverage Spatial
England
Article Number
ARTN 498