Dusp14 protects against hepatic ischaemia-reperfusion injury via Tak1 suppression

Background & Aims: Hepatic ischaemia-reperfusion (I/R) injury is characterised by severe inflammation and extensive cell death. Multiple signalling pathways, including NF-kappa B and mitogen-activated protein kinase (MAPK)/c-Jun NH2-terminal kinase (JNK), have important roles in this process. Identifying the unknown critical regulators of these signalling pathways could provide potential targets for therapeutic application. Dual-specificity phosphatase 14 (DUSP14) acts as a negative regulator of NF-kappa B signalling. However, its function in hepatic I/R injury is unknown. Methods: Hepatocyte-specific Dusp14 knockout (HKO) and transgenic (TG) mice were subjected to hepatic I/R surgery to examine Dusp14 function in vivo. Primary hepatocytes isolated from Dusp14-HKO and Dusp14-TG mice were cultured and subjected to hypoxia/reoxygenation insult in vitro. Inflammatory cytokine production was measured using quantitative reverse transcription PCR and ELISA. Liver damage was analysed using histopathology. Co-immunoprecipitation and pull-down assays followed by Western blot were performed to detect Dusp14 and transforming growth factor (Tgf)-beta-activated kinase 1 (Tak1) interactions. Results: Dusp14 was significantly downregulated in liver tissues from liver transplantation patients and mice subjected to hepatic I/R surgery. Dusp14-HKO and Dusp14-TG mouse models demonstrated that Dusp14 reduced cell death, ameliorated inflammation, and promoted hepatocyte proliferation and/or regeneration. Dusp14 also suppressed NF-kappa B and MAPK signalling via a physical interaction with Tak1, leading to its subsequent inhibition. Tak1 inhibition by 5Z-7-ox abolished Dusp14 function in vivo, indicating that TAK1 is required for Dusp14 function in hepatic I/R injury. Finally, mutant Dusp14 lost the ability to bind Tak1 and failed to protect against hepatic I/R injury. Conclusions: Dusp14 is a protective factor in hepatic I/R injury, and the Dusp14-Tak1-Jnk1/2 regulatory axis is important for the pathogenesis of hepatic I/R injury. Modulation of this axis could be a novel therapeutic strategy to prevent or interfere with this pathological process. Lay summary: Reductions in the level of the protein Dusp14 are closely associated with liver damage caused by inadequate blood supply followed by restoration of blood flow to the liver. Dusp14 protects against liver damage by suppressing the activity of Tak1. Targeting Dusp14 could be a strategy for prevention and treatment of this disease. (C) 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.