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Interplay between interferon regulatory factor 1 and BRD4 in the regulation of PD-L1 in pancreatic stellate cells. Sci Rep 2018 Sep 05;8(1):13225 PMID: 30185888 PMCID: PMC6125340

Pubmed ID

30185888

DOI

10.1038/s41598-018-31658-1

Abstract

The fibrotic reaction is a characteristic feature of human pancreatic ductal adenocarcinoma (PDAC) tumors. It is associated with activation and proliferation of pancreatic stellate cells (PSCs), which are key regulators of fibrosis in vivo. While there is increasing interest in the regulation of PD-L1 expression in cancer and immune cells, the expression and regulation of PD-L1 in other stromal cells, such as PSCs, has not been fully evaluated. Here we show that PSCs in vitro express higher PD-L1 mRNA and protein levels compared to the levels present in PDAC cells. We show that inhibitors targeting bromodomain and extra-terminal (BET) proteins and BRD4 knockdown decrease interferon-γ (IFN-γ)-induced PD-L1 expression in PSCs. We also show that c-MYC, one of the well-established targets of BET inhibitors, does not mediate IFN-γ-regulated PD-L1 expression in PSCs. Instead we show that interferon regulatory factor 1 (IRF1) mediates IFN-γ-induced PD-L1 expression in PSCs. Finally, while we show that BET inhibitors do not regulate IFN-γ-induced IRF1 expression in PSCs, BET inhibitors decrease binding of IRF1 and BRD4 to the PD-L1 promoter. Together, these results demonstrate the interplay between IRF1 and BRD4 in the regulation of PD-L1 in PSCs.

Author List

Ebine K, Kumar K, Pham TN, Shields MA, Collier KA, Shang M, DeCant BT, Urrutia R, Hwang RF, Grimaldo S, Principe DR, Grippo PJ, Bentrem DJ, Munshi HG

Author

Raul A. Urrutia MD Center Director, Professor in the Surgery department at Medical College of Wisconsin




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