title: IRF-1 promotes liver transplant ischemia/reperfusion injury via hepatocyte IL-15/IL-15Rα production.
abstract: Ischemia and reperfusion (I/R) injury following liver transplantation (LTx) is an important problem that significantly impacts clinical outcomes. IFN regulatory factor-1 (IRF-1) is a nuclear transcription factor that plays a critical role in liver injury. Our objective was to determine the immunomodulatory role of IRF-1 during I/R injury following allogeneic LTx. IRF-1 was induced in liver grafts immediately after reperfusion in both human and mouse LTx. IRF-1 contributed significantly to I/R injury because IRF-1-knockout (KO) grafts displayed much less damage as assessed by serum alanine aminotransferase and histology. In vitro, IRF-1 regulated both constitutive and induced expression of IL-15, as well as IL-15Rα mRNA expression in murine hepatocytes and liver dendritic cells. Specific knockdown of IRF-1 in human primary hepatocytes gave similar results. In addition, we identified hepatocytes as the major producer of soluble IL-15/IL-15Rα complexes in the liver. IRF-1-KO livers had significantly reduced NK, NKT, and CD8(+) T cell numbers, whereas rIL-15/IL-15Rα restored these immune cells, augmented cytotoxic effector molecules, promoted systemic inflammatory responses, and exacerbated liver injury in IRF-1-KO graft recipients. These results indicate that IRF-1 promotes LTx I/R injury via hepatocyte IL-15/IL-15Rα production and suggest that targeting IRF-1 and IL-15/IL-15Rα may be effective in reducing I/R injury associated with LTx.
authors.affiliation: Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261;
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Yokota
authors.affiliation: Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261;
authors.forename: Osamu
authors.initials: O
authors.lastname: Yoshida
authors.affiliation: Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261;
authors.forename: Lei
authors.initials: L
authors.lastname: Dou
authors.affiliation: Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261;
authors.forename: Anthony V
authors.initials: AV
authors.lastname: Spadaro
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261;
authors.forename: Kumiko
authors.initials: K
authors.lastname: Isse
authors.affiliation: Center for Biologic Imaging, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261;
authors.forename: Mark A
authors.initials: MA
authors.lastname: Ross
authors.affiliation: Center for Biologic Imaging, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261;
authors.forename: Donna B
authors.initials: DB
authors.lastname: Stolz
authors.affiliation: Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261;
authors.forename: Shoko
authors.initials: S
authors.lastname: Kimura
authors.affiliation: Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261;
authors.forename: Qiang
authors.initials: Q
authors.lastname: Du
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261;
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Demetris
authors.affiliation: Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261; and.
authors.forename: Angus W
authors.initials: AW
authors.lastname: Thomson
authors.affiliation: Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261; Liver Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, PA 15261 gellerda@upmc.edu.
authors.forename: David A
authors.initials: DA
authors.lastname: Geller
mesh_terms: D064591:Allografts; D000818:Animals; D018929:Cell Culture Techniques; D016923:Cell Death / Q000235:genetics; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D020868:Gene Silencing; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D050856:Interferon Regulatory Factor-1 / Q000235:genetics*; D019409:Interleukin-15 / Q000235:genetics / Q000378:metabolism*; D053720:Interleukin-15 Receptor alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016031:Liver Transplantation / Q000009:adverse effects*; D016131:Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D011485:Protein Binding; D015427:Reperfusion Injury / Q000235:genetics* / Q000378:metabolism*
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D050856:Interferon Regulatory Factor-1; D019409:Interleukin-15; D053720:Interleukin-15 Receptor alpha Subunit