Down-regulation of microRNA-138 improves immunologic function via negatively targeting p53 by regulating liver macrophage in mice with acute liver failure.

You-Qiang Wang,Yong-Can Guo,Qin-Wei Yuan,Peng Liu,You-Yu Lan

doi:10.1042/bsr20190763

Abstract

MicroRNAs (miRNAs) have been frequently identified as key mediators in almost all developmental and pathological processes, including those in the liver. The present study was conducted with aims of investigating the role of microRNA-138 (miR-138) in acute liver failure (ALF) via a mechanism involving p53 and liver macrophage in a mouse model. The ALF mouse model was established using C57BL/6 male mice via tail vein injection of Concanamycin A (Con A) solution. The relationship between miR-138 and p53 was tested. The mononuclear macrophages were infected with mimic and inhibitor of miR-138 in order to identify roles of miR-138 in p53 and levels of inflammatory factors. Reverse transcription quantitative polymerase chain reaction (RT-qPCR), Western blot analysis and ELISA were conducted in order to determine the levels of miR-138, inflammatory factors, and p53 during ALF. The results showed an increase in the levels of miR-138 and inflammatory factors in ALF mice induced by the ConA as time progressed and reached the peak at 12 h following treatment with ConA, while it was on the contrary when it came to the level of p53. Dual-luciferase reporter gene assay revealed that p53 was a target gene of miR-138. Furthermore, the results from the in vitro transfection experiments in primary macrophages of ALF mouse showed that miR-138 down-regulated p53 and enhanced levels of inflammatory factors; thus, improving immune function in ALF mice. In conclusion, by negatively targeting p53, the decreased miR-138 improves immunologic function by regulating liver macrophage in mouse models of ALF.

Highlights

Liver failure is a clinical syndrome that is the final stage during the progression of liver damage due to a variety of etiological factors and is characterized by ascites, jaundice, hepatic encephalopathy, and a trend of bleeding [1]
HE staining was used identify the pathological characteristics of Acute liver failure (ALF) in mice, and the findings revealed that in comparison with the control group, there were no significant changes in liver pathology in the ConA 0 h group; the ConA 1 h group exhibited only small dispersed polymorphonuclear leukocytes infiltration and rare necrotic foci; small and scattered inflammatory necrosis with polymorphonuclear leukocyte infiltration was found in the ConA 3–6 h group; there was obvious patchy necrosis and portal congestion and coagulation phenomenon in the ConA 12–24 h group (Figure 1A)
The present study highlights the effects of miR-138 on the immune function of mice with ALF, and the findings were highly suggestive of the concept that the negative regulation of p53 by downregulated miR-138 could affect the function of liver macrophages and enhance the immune function of mice with ALF

Summary

Introduction

Liver failure is a clinical syndrome that is the final stage during the progression of liver damage due to a variety of etiological factors and is characterized by ascites, jaundice, hepatic encephalopathy, and a trend of bleeding [1]. Acute liver failure (ALF) is a serious clinical syndrome, which develops over a short period of time, associated with significant coagulopathy [2]. The survival rate (spontaneous liver regeneration) of patients with ALF is 40%, but this varies significantly with the etiology of ALF [4]. The severity of acute live injury and the clinical outcome of ALF are dependent on the intensity of the uncontrolled stimulation of innate immune responses, which is a dominant factor in the pathogenesis of ALF [5].

Methods

Results

Discussion

Conclusion