Basic Study
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World J Gastroenterol. Jul 14, 2022; 28(26): 3150-3163
Published online Jul 14, 2022. doi: 10.3748/wjg.v28.i26.3150
Activation of natural killer T cells contributes to Th1 bias in the murine liver after 14 d of ethinylestradiol exposure
Meng-Zhi Zou, Wei-Chao Kong, Heng Cai, Meng-Tao Xing, Zi-Xun Yu, Xin Chen, Lu-Yong Zhang, Xin-Zhi Wang
Meng-Zhi Zou, Wei-Chao Kong, Heng Cai, Zi-Xun Yu, Xin Chen, Lu-Yong Zhang, Xin-Zhi Wang, New Drug Screening Center, China Pharmaceutical University, Nanjing 210009, Jiangsu Province, China
Meng-Tao Xing, Department of Pharmacology, China Pharmaceutical University, Nanjing 210009, Jiangsu Province, China
Lu-Yong Zhang, Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou 510006, Guangdong Province, China
Author contributions: Zou MZ and Kong WC contributed equally to the work; Zou MZ, Kong WC, Yu ZX, and Chen X performed the experiments, collected data, and analyzed the data; Xing MT, Zhang LY, and Wang XZ contributed to the guidance of experiments and the final manuscript; Wang XZ and Xing MT designed the study; Wang XZ, Xing MT, Zou MZ and Cai H wrote the manuscript; All the authors have reviewed and approved the final version of the manuscript.
Supported by the National Natural Science Foundation of China, No. 82073948 and 81703626; and National Innovation and Entrepreneurship Training Program for Undergraduate, No. 202210316040Z.
Institutional animal care and use committee statement: All animal experiments involved in this study were performed under the Ethical Committee of China Pharmaceutical University and the Laboratory Animal Management Committee of Jiangsu Province guidelines (Approval No.: 2021-10-003).
Conflict-of-interest statement: All authors have nothing to disclose.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read 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: Xin-Zhi Wang, PhD, Associate Research Scientist, New Drug Screening Center, China Pharmaceutical University, No. 24 Tongjiaxiang, Nanjing 210009, Jiangsu Province, China. wangxz@cpu.edu.cn
Received: October 26, 2021
Peer-review started: October 26, 2021
First decision: April 16, 2022
Revised: April 25, 2022
Accepted: May 22, 2022
Article in press: May 22, 2022
Published online: July 14, 2022
Processing time: 260 Days and 4.9 Hours
ARTICLE HIGHLIGHTS
Research background

Cholestasis is mild and common during liver diseases but is also a crucial triggering element of severe hepatopathy. As the predominant component of oral contraceptives (OCs) and hormone replacement therapy, 17α-ethinylestradiol (EE) is used as a model drug to induce murine intrahepatic cholestasis (IHC). The clinical counterpart of EE-induced IHC includes women who are taking OCs, postmenopausal replacement therapy, and susceptible pregnant women.

Research motivation

The significance of the local immune microenvironment in the liver has been emphasized because estrogens are immunomodulators that are metabolized in the liver.

Research objectives

The aim of the present study was to investigate the effects and mechanisms of natural killer T (NKT) cells in a murine model of EE-induced cholestatic hepatotoxicity.

Research methods

Male C57BL/6J mice or invariant NKT (iNKT) cell deficiency (Jα18-/- mice) were administered with EE (10 mg/kg, subcutaneous) for 14 d.

Research results

Both Th1 and Th2 cytokines produced by NKT cells increased in the liver skewing toward a Th1 bias. The expression of the chemokine/chemokine receptor Cxcr6/Cxcl16, toll-like receptors, Ras/Rad, and PI3K/Bad signaling was upregulated after EE administration. EE also influenced bile acid synthase Cyp7a1, Cyp8b1, and tight junctions ZO-1 and Occludin, which might be associated with EE-induced cholestasis. iNKT cell deficiency (Jα18-/- mice) robustly alleviated cholestatic liver damage and lowered the expression of the abovementioned signaling pathways.

Research conclusions

The present study demonstrated that hepatic NKT cells play a pathogenic role in EE-induced intrahepatic cholestasis, contributing to the development of the IHC mechanisms and the potential treatment targeting NKT cells.

Research perspectives

Hepatic NKT cells and their Th1 cytokine production play a pathogenic role in a 14-d murine model of EE-induced intrahepatic cholestasis.