Basic Study
Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jan 14, 2018; 24(2): 216-225
Published online Jan 14, 2018. doi: 10.3748/wjg.v24.i2.216
β-arrestin 2 attenuates lipopolysaccharide-induced liver injury via inhibition of TLR4/NF-κB signaling pathway-mediated inflammation in mice
Meng-Ping Jiang, Chun Xu, Yun-Wei Guo, Qian-Jiang Luo, Lin Li, Hui-Ling Liu, Jie Jiang, Hui-Xin Chen, Xiu-Qing Wei
Meng-Ping Jiang, Chun Xu, Yun-Wei Guo, Qian-Jiang Luo, Lin Li, Hui-Ling Liu, Jie Jiang, Xiu-Qing Wei, Department of Digestive Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, Guangdong Province, China
Chun Xu, Hui-Xin Chen, Department of Digestive Diseases, Huizhou Municipal Center Hospital, Huizhou 516002, Guangdong Province, China
Author contributions: Jiang MP, Xu C and Guo YW contributed equally to this work and performed most of the experiments; Luo QJ, Li L, Liu HL and Jiang J bred the animals and collected the animal material; Chen HX analyzed the data; and Wei XQ designed the study and wrote the paper.
Supported by the National Natural Science Foundation of China, No. 81470848; and the Breeding Foundation for Young Pioneers’ Research of Sun Yat-sen University, No. 14ykpy27.
Institutional review board statement: The study was reviewed and approved by the Institutional Review Board of the Third Affiliated Hospital of Sun Yat-sen University.
Institutional animal care and use committee statement: All procedures were conducted in accordance with The Guide for the Care and Use of Laboratory Animals and were approved by the Institutional Animal Care and Use Committee of The Third Affiliated Hospital of Sun Yat-sen University.
Conflict-of-interest statement: The authors declare that there is no conflict of interest regarding the publication of this paper.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Xiu-Qing Wei, MD, PhD, Department of Digestive Diseases, The Third Affiliated Hospital of Sun Yat-Sen University, No. 600, Tianhe Road, Tianhe District, Guangzhou 510630, Guangdong Province, China. weixq@mail.sysu.edu.cn
Telephone: +86-20-85252056 Fax: +86-20-85253336
Received: September 11, 2017
Peer-review started: September 12, 2017
First decision: October 18, 2017
Revised: November 3, 2017
Accepted: November 22, 2017
Article in press: November 22, 2017
Published online: January 14, 2018
ARTICLE HIGHLIGHTS
Research background

Lipopolysaccharide (LPS)-induced liver injury serves as the pathological basis of varied hepatic diseases. LPS does not directly harm hepatocytes, while Kupffer cells serve as the key components of LPS-induced injury through secretion of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β. β-arrestin 2 is a protein that plays an important role in regulating the TLR4/NF-κB signaling pathway, which plays a critical role in inflammation. However, the role of β-arrestin 2 in LPS-induced liver injury remains unclear.

Research motivation

The inhibition of LPS-induced inflammation via regulation of the TLR4/NF-κB signaling pathway may be a therapeutic method for modulating LPS-induced injury. β-arrestin 2 is a protein that plays an important role in regulating the TLR4/NF-κB signaling pathway. Therefore, we hypothesized that β-arrestin 2 can play a role in the prevention of LPS-induced liver injury.

Research objectives

The objective of this study was to investigate the role and the possible mechanism of β-arrestin 2 in LPS-induced liver injury in vivo and in vitro. This is the first study to show that β-arrestin 2 attenuated LPS-induced liver injury in a mouse model induced by injection of pure LPS. β-arrestin 2 may serve as a therapeutic target for the prevention and treatment of LPS-induced liver injury.

Research methods

The animal model was established via intraperitoneal injection of LPS or physiological sodium chloride solution in male β-arrestin 2+/+ and β-arrestin 2-/- C57BL/6J mice. Blood samples and liver tissues were collected for analysis of liver injury and levels of pro-inflammatory cytokines. Extracts from the cultured mouse macrophage cell line RAW264.7 treated with various conditions were collected to analyze the production of pro-inflammatory cytokines and expression of key molecules involved in the TLR4/NF-κB signaling pathway.

Research results

The β-arrestin 2 knockout mice displayed more severe LPS-induced liver injury and significantly higher levels of pro-inflammatory cytokines, including IL-1β, IL-6, TNF-α, and IL-10, than the wild-type mice. Compared with the control group, pro-inflammatory cytokines, including IL-1β, IL-6, TNF-α, and IL-10, produced by the β-arrestin 2 siRNA-treated RAW264.7 cells were significantly higher at 6 h after treatment with LPS. The key molecules involved in the TLR4/NF-κB signaling pathway were also increased, including phospho-IκBα and phosho-p65.

Research conclusions

We hypothesized that β-arrestin 2 could protect liver tissue from LPS-induced injury via inhibition of TLR4/NF-κB-mediated inflammation. This hypothesis was proven using an animal model of LPS-induced liver injury in male β-arrestin 2+/+ and β-arrestin 2-/- C57BL/6J mice and a cell model using the mouse macrophage cell line RAW264.7. These findings may be helpful for the prevention and treatment of LPS-induced liver injury in future clinical practice via strengthening the function of β-arrestin 2. However, further study on the exact role and possible mechanism is still needed.

Research perspectives

Studies of the role of β-arrestin 2 agonists and methods of up-regulation of β-arrestin 2 in the prevention and treatment of LPS-induced liver injury should be performed.