科学研究
20170905 Dusp14 protects against hepatic ischemia-reperfusion injury via Tak1 suppression.
发布时间:2017-09-30  来源:  阅读次数:

J Hepatol.2017 Sep 5. pii: S0168-8278(17)32275-4. doi: 10.1016/j.jhep.2017.08.032. [Epub ahead of print]

Dusp14 protects against hepatic ischemia-reperfusion injury via Tak1 suppression.

Wang X1,Mao W1,Fang C1,Tian S1,Zhu X1,Yang L1,Huang Z2,Li H3.

Abstract

BACKGROUND AND AIMS:

Hepaticischemia-reperfusion(I/R) injury is characterized by severe inflammation and extensive cell death. Multiple signaling pathways, including NF-κB and MAPK/Jnk, play important roles in this process. Identifying the unknown critical regulators of these signaling pathways may provide potential targets for therapeutic application. Dual specific phosphatase 14 (DUSP14) acts as a negative regulator of NF-κB signaling. However, the function of Dusp14 in hepatic I/R injury remains unknown.

METHODS:

Hepatocyte-specific Dusp14 knockout (HKO) and transgenic (TG) mice were subjected to hepatic I/R surgery to examineDusp14 function in vivo. Primary hepatocytes isolated from Dusp14-HKO and Dusp14-TG mice were cultured and subjected to hypoxia/reoxygenation (H/R) insult in vitro. Inflammatory cytokine production was measured using quantitative RT-PCR and ELISA. Liver damage was analyzed using histopathology. Co-immunoprecipitation and pull-down assays followed by Western blot were performed to detect Dusp14 and Tak1 interactions.

RESULTS:

Dusp14was 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/regeneration. Dusp14 also suppressed NF-κB and MAPK signaling via a physical interaction withTak1, leading to its subsequent inhibition. Tak1 was required for Dusp14 function in hepatic I/R injury because Tak1 inhibition by 5Z-7-ox abolished Dusp14 function in vivo. Finally, mutant Dusp14 lost the ability to bind Tak1 and failed to protect against hepatic I/Rinjury.

CONCLUSION:

Dusp14is 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 may be a novel strategy to prevent or interfere with this pathological process.

LAY SUMMARY:

Reduction of Dusp14 protein is tightly associates with liver damage caused by inadequate blood supply followed by restoring the flow of blood to the liver. Dusp14 protects against liver damage by suppressing the Tak1 activity. Targeting Dusp14 can be a strategy for precaution and treatment of this disease.

Copyright (c) 2017. Published by Elsevier B.V.

KEYWORDS:

Dusp14; Tak1; hepatic ischemia/reperfusion

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