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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