Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 293, Issue 7, Pages 2422-2437Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA117.000698
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Funding
- Kennedy Trust for Rheumatology Research
- Arthritis Research UK [20522]
- National Institute of Health Research Oxford Biomedical Research Unit
- Cancer Research UK
- Rosetrees Trust
- Medical Research Council CGAT [G1000902]
- Abbvie
- Bayer Healthcare
- Boehringer Ingelheim
- Canadian Institutes for Health Research
- Canadian Foundation for Innovation
- Eli Lilly and Company
- Genome Canada
- Ontario Ministry of Economic Development and Innovation
- Janssen
- Novartis Research Foundation
- Pfizer
- Takeda
- Wellcome Trust
- People Programme (Marie Curie Actions) of European Union Seventh Framework Programme under Research Executive Agency (REA) [609305]
- Rosetrees Trust [M289-F1, M289] Funding Source: researchfish
- Versus Arthritis [20522] Funding Source: researchfish
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Natural killer (NK) cells are innate lymphocytes, important in immune surveillance and elimination of stressed, transformed, or virus-infected cells. They critically shape the inflammatory cytokine environment to orchestrate interactions of cells of the innate and adaptive immune systems. Some studies have reported that NK cell activation and cytokine secretion are controlled epigenetically but have yielded only limited insight into the mechanisms. Using chemical screening with small-molecule inhibitors of chromatin methylation and acetylation, further validated by knockdown approaches, we here identified Jumonji-type histone H3K27 demethylases as key regulators of cytokine production in human NK cell subsets. The prototypic JMJD3/UTX (Jumonji domain-containing protein 3) H3K27 demethylase inhibitor GSK-J4 increased global levels of the repressive H3K27me3 mark around transcription start sites of effector cytokine genes. Moreover, GSK-J4 reduced IFN-gamma, TNF alpha, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukin-10 levels in cytokine-stimulated NK cells while sparing their cytotoxic killing activity against cancer cells. The anti-inflammatory effect of GSK-J4 in NK cell subsets, isolated from peripheral blood or tissue from individuals with rheumatoid arthritis (RA), coupled with an inhibitory effect on formation of bone-resorbing osteoclasts, suggested that histone demethylase inhibition has broad utility for modulating immune and inflammatory responses. Overall, our results indicate that H3K27me3 is a dynamic and important epigenetic modification during NK cell activation and that JMJD3/UTX-driven H3K27 demethylation is critical for NK cell function.
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