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©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
Hypoxia inducible factor 1α promotes interleukin-1 receptor antagonist expression during hepatic ischemia-reperfusion injury
Zhao-Yang Wang, Yu Liu, Shi-Peng Li, Jian-Jun Li, Zhen Zhang, Xue-Chun Xiao, Yang Ou, Hang Wang, Jin-Zhen Cai, Shuang Yang
Zhao-Yang Wang, Jian-Jun Li, Xue-Chun Xiao, Yang Ou, Hang Wang, Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, Medical College of Nankai University, Tianjin 300071, China
Yu Liu, Department of Internal Medicine, Wangdingdi Hospital, Tianjin 300071, China
Shi-Peng Li, Liver Transplant Center of Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
Zhen Zhang, Institute of Clinical Medicine, Jiangxi Provincial People’s Hospital Affiliated to Nanchang University, Nanchang 330006, Jiangxi Province, China
Jin-Zhen Cai, Organ Transplantation Center, Affiliated Hospital of Qingdao University, Qingdao 266000, Shandong Province, China
Shuang Yang, Institute of Transplantation Medicine, Tianjin First Central Hospital, Nankai University, Tianjin 300071, China
Author contributions: Wang ZY, Li SP, Cai JZ, and Yang S designed and coordinated the study; Wang ZY, Liu Y, Li JJ, Zhang Z, Xiao XC, Ou Y, and Wang H performed the experiments, and acquired and analyzed the data; Wang ZY and Yang S interpreted the data; Wang ZY and Yang S wrote the manuscript; and all authors approved the final version of the article.
Supported by the National Natural Science Foundation of China, No. 81670600.
Institutional animal care and use committee statement: The animal study protocol was approved by the Animal Ethical and Welfare Committee (protocol code: IRM-DWLL-2020173 and date of approval: September 15, 2020).
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have reviewed the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (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:
https://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Shuang Yang, PhD, Professor, Institute of Transplantation Medicine, Tianjin First Central Hospital, Nankai University, No. 94 Weijin Road, Nankai District, Tianjin 300071, China. yangshuang@mail.nankai.edu.cn
Received: May 30, 2022
Peer-review started: May 30, 2022
First decision: August 1, 2022
Revised: August 16, 2022
Accepted: September 21, 2022
Article in press: September 21, 2022
Published online: October 14, 2022
ARTICLE HIGHLIGHTS
Research background
Ischemia-reperfusion injury (IRI) is associated with transplant failures, graft dysfunction, and a relatively poor prognosis. Interleukin-1 receptor antagonists (IL-1ra) play an important role in protecting the liver from IRI. However, the mechanism of its regulatory expression remains unclear.
Research motivation
Inhibition of hepatic inflammation by promoting the expression of IL-1ra is one of the key targets for the treatment of hepatic IRI.
Research objectives
To investigate the regulatory mechanism of hepatocyte-derived IL-1ra expression in the process of hepatic IRI to provide a therapeutic target for hepatic IRI.
Research methods
A 70% hepatic IRI model was established in mice, and AML12 cells were subjected to hypoxia/ reoxygenation for the simulation of IRI in vitro. The Il-1ra promoter-reporter system was constructed to detect the regulatory effect of hypoxia. The ischemic preconditioning (IP) model was established to investigate its regulatory effect on IL-1ra.
Research results
IL-1ra is a key regulator of hepatic IRI. Il-1ra expression was significantly up-regulated after hepatic IRI in vivo and in vitro. Hypoxia inducible factor (HIF)-1α regulates Il-1ra transcription during hypoxia. IP prevents hepatic IRI by inducing the expression of IL-1ra, which is mediated by HIF-1α.
Research conclusions
Ischemia or hypoxia leads to increased IL-1ra expression through HIF-1α. In addition, IP protects the hepatic tissue from IRI through the HIF-1α-IL-1ra pathway.
Research perspectives
HIF-1α-IL-1ra pathway is a potential mechanism of hepatic protection during hepatic IRI, and also a key target for the treatment of hepatic IRI.
