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

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.

SUBMITTER: Perucha E 

PROVIDER: S-EPMC6353904 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature