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

Journal article

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.

Authors: Yee, D; Shah, K; Coles, M; Sharp, T; Lagos, D

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: American Society for Biochemistry and Molecular Biology
• Journal: Journal of Biological Chemistry
• Volume: 292
• Issue: 50
• Pages: 20683-20693
• Publication date: 2017-10-24
• Acceptance date: 2017-10-23
• DOI: 10.1074/jbc.m117.809053
• EISSN: 1083-351X
• ISSN: 0021-9258
• Pmid: 29066622
• Language: English
• Keywords: microscopy, fluorescence; tumor necrosis factor-alpha; interferon-gamma; genes, reporter; gene expression profiling; humans; recombinant proteins; dermis; kinetics; 3' untranslated regions; response elements; microRNAs; cells, cultured; gene expression regulation; binding sites; base sequence; RNA interference; B7-H1 antigen; RNA, small interfering; endothelium, lymphatic