The cholesterol biosynthesis pathway regulates IL-10 expression in human Th1 cells.
Esperanza PeruchaRossella MelchiottiJack A BibbyWing WuKlaus Stensgaard FrederiksenCeri A RobertsZoe HallGaelle LeFriecKevin A RobertsonPaul LavenderJens Gammeltoft GerwienLeonie S TaamsJulian L GriffinEmanuele de RinaldisLisa G M van BaarsenClaudia KemperPeter GhazalAndrew P CopePublished in: Nature communications (2019)
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.
Keyphrases
- endothelial cells
- gene expression
- poor prognosis
- low density lipoprotein
- rheumatoid arthritis
- inflammatory response
- induced pluripotent stem cells
- immune response
- dna methylation
- binding protein
- pluripotent stem cells
- cell wall
- oxidative stress
- single cell
- induced apoptosis
- regulatory t cells
- deep learning
- cell proliferation
- cell cycle arrest
- long non coding rna
- drug induced