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

• Published in: Nature communications Vol. 10; no. 1; p. 498
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 30-01-2019; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 13/21; 13/31; 38; 45/61; 45/77; 45/88; 45/90; 631/250/127/1213; 631/250/1619/554/1898/1271; 631/443/319/2723; 692/4023/1670/498; 82/58; Arthritis; Atorvastatin; Atorvastatin - pharmacology; Biosynthesis; c-Maf protein; CD4 antigen; Cholesterol; Cholesterol - biosynthesis; Gene expression; Human behavior; Humanities and Social Sciences; Humans; Hydroxycholesterols - pharmacology; Inflammatory diseases; Inflammatory response; Interferon-gamma - metabolism; Interleukin 1; Interleukin 10; Interleukin-10 - metabolism; Lipid metabolism; Lymphocytes; Lymphocytes T; Metabolism; multidisciplinary; Phenotypes; Rheumatoid arthritis; Science; Science (multidisciplinary); Switching; Th1 Cells - drug effects; Th1 Cells - metabolism; Transcription; γ-Interferon
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-08332-9

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.
Metabolic pathways are increasingly recognized as crucial determinants of T cell function. Here the authors show that the balance between IFNγ and IL-10 production in human CD4 T cells is modulated by the cholesterol biosynthetic pathway.