IRF-1 promotes liver transplant ischemia/reperfusion injury via hepatocyte IL-15/IL-15Rα production

• Published in: The Journal of immunology (1950) 2015-06, Vol.194 (12), p.6045-6056
• Main Authors: Yokota, Shinichiro, Yoshida, Osamu, Dou, Lei, Spadaro, Anthony V, Isse, Kumiko, Ross, Mark A, Stolz, Donna B, Kimura, Shoko, Du, Qiang, Demetris, Anthony J, Thomson, Angus W, Geller, David A
• Format: Article
• Language: English
• Subjects: Allografts; Animals; Cell Culture Techniques; Cell Death - genetics; Cytokines - metabolism; Dendritic Cells - immunology; Dendritic Cells - metabolism; Disease Models, Animal; Gene Expression Regulation; Gene Knockout Techniques; Gene Silencing; Hepatocytes - metabolism; Humans; Inflammation Mediators - metabolism; Interferon Regulatory Factor-1 - genetics; Interleukin-15 - genetics; Interleukin-15 - metabolism; Interleukin-15 Receptor alpha Subunit - genetics; Interleukin-15 Receptor alpha Subunit - metabolism; Liver - immunology; Liver - metabolism; Liver - pathology; Liver Transplantation - adverse effects; Lymphocyte Subsets - immunology; Lymphocyte Subsets - metabolism; Male; Mice; Mice, Knockout; Models, Biological; Protein Binding; Reperfusion Injury - genetics; Reperfusion Injury - metabolism
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1402505

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.