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

被引：0

作者：

Esperanza Perucha

Rossella Melchiotti

Jack A Bibby

Wing Wu

Klaus Stensgaard Frederiksen

Ceri A. Roberts

Zoe Hall

Gaelle LeFriec

Kevin A. Robertson

Paul Lavender

Jens Gammeltoft Gerwien

Leonie S. Taams

Julian L. Griffin

Emanuele de Rinaldis

Lisa G. M. van Baarsen

Claudia Kemper

Peter Ghazal

Andrew P. Cope

机构：

[1] King’s College London,Academic Department of Rheumatology

[2] King’s College London,Department of Inflammation Biology, School of Immunology and Microbial Sciences, Centre for Inflammation Biology and Cancer Immunology

[3] Guy’s and St Thomas’ NHS Foundation Trust and King’s College London,National Institute for Health Research Biomedical Research Centre

[4] Novo Nordisk A/S,Global Drug Discovery

[5] University of Cambridge,Department of Biochemistry and the Cambridge Systems Biology Centre

[6] King’s College London,MRC Centre for Transplantation

[7] University of Edinburgh,Division of Infection and Pathway Medicine

[8] King’s College London,School of Immunology and Microbial Sciences

[9] University of Amsterdam,Amsterdam Rheumatology and immunology Center (ARC), Department of Rheumatology and Clinical Immunology, Amsterdam UMC

[10] University of Amsterdam,Department of Experimental Immunology, Amsterdam UMC

[11] National Institutes of Health (NIH),Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute (NHLBI)

[12] University of Lübeck,Institute for Systemic Inflammation Research

[13] University of Cardiff,Systems Immunity Research Institute, Medical School

[14] NHS Blood and Transplant,Cellular and Molecular Therapy

[15] Eli Lilly,Rheumatology NEC

来源：

Nature Communications | / 10卷

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摘要：

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.

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