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MicroRNA-513 Regulates B7-H1 Translation and Is Involved in IFN--Induced B7-H1 Expression in Cholangiocytes^1,2

Ai-Yu Gong^*, Rui Zhou^*, Guoku Hu^*, Xiaoqing Li^*, Patrick L. Splinter, Steven P. O'Hara, Nicholas F. LaRusso, Garrett A. Soukup, Haidong Dong and Xian-Ming Chen^3,*

^* Department of Medical Microbiology and Immunology and Department of Biomedical Sciences, Creighton University Medical Center, Omaha, NE 68178; and Division of Gastroenterology and Hepatology and Department of Immunology, Mayo Clinic College of Medicine, Rochester, MN 55905

Biliary epithelial cells (cholangiocytes) respond to proinflammatory cytokines such as IFN- and actively participate in the regulation of biliary inflammatory response in the liver. B7-H1 (also known as CD274 or PD-L1) is a member of the B7 costimulatory molecules and plays a critical immunoregulatory role in cell-mediated immune responses. In this study, we show that resting human cholangiocytes in culture express B7-H1 mRNA, but not B7-H1 protein. IFN- induces B7-H1 protein expression and alters the microRNA (miRNA) expression profile in cholangiocytes. Of those IFN--down-regulated miRNAs, we identified microRNA-513 (miR-513) with complementarity to the 3'-untranslated region of B7-H1 mRNA. Targeting of the B7-H1 3'-untranslated region by miR-513 results in translational repression. Transfection of cholangiocytes with an antisense oligonucleotide to miR-513 induces B7-H1 protein expression. Additionally, transfection of miR-513 precursor decreases IFN--induced B7-H1 protein expression and consequently influences B7-H1-associated apoptotic cell death in cocultured Jurkat cells. Thus, miR-513 regulates B7-H1 translation and is involved in IFN--induced B7-H1 expression in human cholangiocytes, suggesting a role for miRNA-mediated gene silencing in the regulation of cholangiocyte response to IFN-.

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¹ This work was supported by National Institutes of Health Grants AI071321 and by the Nebraska Tobacco Settlement Biomedical Research Program LB692 (to X.-M.C.).

² The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

³ Address correspondence and reprint requests to Dr. Xian-Ming Chen, Department of Medical Microbiology and Immunology, Creighton University Medical Center, 2500 California Plaza, Omaha, NE 68178. E-mail address: xianmingchen{at}creighton.edu

⁴ Abbreviations used in this paper: miRNA, microRNA; DAPI, 4',6-diamidino-2-phenylindole; HIBEpiC, human intrahepatic biliary epithelial cell; miR-513, microRNA-513; PD-1, programmed death receptor-1; siRNA, small interfering RNA; UTR, untranslated region.

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