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J Biol Chem. 2017 Dec 15;292(50):20683-20693. doi: 10.1074/jbc.M117.809053. Epub 2017 Oct 24.

MicroRNA-155 induction via TNF-α and IFN-γ suppresses expression of programmed death ligand-1 (PD-L1) in human primary cells.

Author information

1
From the Centre for Immunology and Infection, Department of Biology and Hull York Medical School, University of York, York YO10 5DD and.
2
the Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, United Kingdom.
3
From the Centre for Immunology and Infection, Department of Biology and Hull York Medical School, University of York, York YO10 5DD and dimitris.lagos@york.ac.uk.

Abstract

Programmed death ligand-1 (PD-L1) is a critical regulator of T cell function contributing to peripheral immune tolerance. Although it has been shown that posttranscriptional regulatory mechanisms control PD-L1 expression in cancer, it remains unknown whether such regulatory loops operate also in non-transformed cells. Here we studied PD-L1 expression in human dermal lymphatic endothelial cells (HDLECs), which play key roles in immunity and cancer. Treatment of HDLECs with the pro-inflammatory cytokines IFN-γ and TNF-α synergistically up-regulated PD-L1 expression. IFN-γ and TNF-α also affected expression of several microRNAs (miRNAs) that have the potential to suppress PD-L1 expression. The most highly up-regulated miRNA following IFN-γ and TNF-α treatment in HDLECs was miR-155, which has a central role in the immune system and cancer. Induction of miR-155 was driven by TNF-α, the effect of which was significantly enhanced by IFN-γ. The PD-L1 3'-UTR contains two functional miR-155-binding sites. Endogenous miR-155 controlled the kinetics and maximal levels of PD-L1 induction upon IFN-γ and TNF-α treatments. We obtained similar findings in dermal fibroblasts, demonstrating that the IFN-γ/TNF-α/miR-155/PD-L1 pathway is not restricted to HDLECs. These results reveal miR-155 as a critical component of an inflammation-induced regulatory loop controlling PD-L1 expression in primary cells.

KEYWORDS:

PD-L1; endothelial cell; fibroblast; immune checkpoint inhibitors; inflammation; interferon; lymphatic endothelial cells; miR-155; microRNA (miRNA)

PMID:
29066622
PMCID:
PMC5733604
DOI:
10.1074/jbc.M117.809053
[Indexed for MEDLINE]
Free PMC Article

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