Nature communications · 2019
The cholesterol biosynthesis pathway regulates IL-10 expression in human Th1 cells.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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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
Аннотация
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.