Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

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.

Original publication

DOI

10.1074/jbc.M117.809053

Type

Journal article

Journal

J Biol Chem

Publication Date

15/12/2017

Volume

292

Pages

20683 - 20693

Keywords

PD-L1, endothelial cell, fibroblast, immune checkpoint inhibitors, inflammation, interferon, lymphatic endothelial cells, miR-155, microRNA (miRNA), 3' Untranslated Regions, B7-H1 Antigen, Base Sequence, Binding Sites, Cells, Cultured, Dermis, Endothelium, Lymphatic, Gene Expression Profiling, Gene Expression Regulation, Genes, Reporter, Humans, Interferon-gamma, Kinetics, MicroRNAs, Microscopy, Fluorescence, RNA Interference, RNA, Small Interfering, Recombinant Proteins, Response Elements, Tumor Necrosis Factor-alpha