Copyright
©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
Processing time: 134 Days and 15.4 Hours
BACKGROUND
Ischemia-reperfusion injury (IRI) is a major risk associated with liver surgery and transplantation, and its pathological mechanism is complex. Interleukin-1 receptor antagonist (IL-1ra) can protect the liver from IRI. However, the regulatory mechanism of IL-1ra expression is still unclear.
AIM
To identify the mechanism that could protect the liver in the early stage of IRI.
METHODS
To screen the key genes in hepatic IRI, we performed RNA sequencing and gene enrichment analysis on liver tissue from mice with hepatic IRI. Subsequently, we verified the expression and effect of IL-1ra in hepatic IRI. We also used promoter mutagenesis and chromatin immunoprecipitation assay to search for the transcriptional regulatory sites of hypoxia-inducible factor (HIF)-1α. Finally, to explore the protective mechanism of ischemic preconditioning (IP), we examined the expression of HIF-1α and IL-1ra after IP.
RESULTS
We identified IL-1ra as a key regulator in hepatic IRI. The expression of IL-1ra was significantly upregulated after hepatic IRI both in vivo and in vitro. Furthermore, we found that HIF-1α regulated Il-1ra transcription in response to hypoxia. Increased HIF-1α accumulation promoted IL-1ra expression, whereas inhibition of HIF-1α exhibited the opposite effect. We also confirmed a predominant role for hypoxia response element in the regulation of Il1ra transcription by HIF-1α activation. Of note, we demonstrated that IP protects against hepatic IRI by inducing IL-1ra expression, which is mediated through HIF-1α.
CONCLUSION
We demonstrated that ischemia or hypoxia leads to increased expression of IL-1ra through HIF-1α. Importantly, IP protects the liver from IRI via the HIF-1α–IL-1ra pathway.
Core Tip: Ischemia-reperfusion injury (IRI) is a major risk associated with liver surgery and transplantation, and its pathological mechanism is complex. Interleukin-1 receptor antagonist (IL-1ra) can protect the liver from IRI. The expression of IL-1ra was significantly upregulated after IRI in mice. Hypoxia promoted the expression of IL-1ra. Hypoxia-inducible factor (HIF)-1α accumulation contributed to increased Il-1ra transcription. Ischemic preconditioning protected the liver from IRI via the HIF-1α-IL-1ra pathway.
