Basic Study
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Feb 7, 2015; 21(5): 1531-1545
Published online Feb 7, 2015. doi: 10.3748/wjg.v21.i5.1531
Interleukin-22 ameliorates liver fibrogenesis by attenuating hepatic stellate cell activation and downregulating the levels of inflammatory cytokines
Dong-Hong Lu, Xiao-Yun Guo, Shan-Yu Qin, Wei Luo, Xiao-Li Huang, Mei Chen, Jia-Xu Wang, Shi-Jia Ma, Xian-Wen Yang, Hai-Xing Jiang
Dong-Hong Lu, Xiao-Yun Guo, Shan-Yu Qin, Wei Luo, Xiao-Li Huang, Mei Chen, Jia-Xu Wang, Shi-Jia Ma, Xian-Wen Yang, Hai-Xing Jiang, Department of Gastroenterology, The First Affiliated Hospital, Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
Author contributions: Lu DH, Guo XY, Qin SY, Luo W performed the experiments; Lu DH analyzed the data; Lu DH, Huang XL, Chen M, Wang JX, Ma SJ, Yang XW contributed to the reagents, materials, and analysis tools; Lu DH wrote the paper; Jiang HX designed this experiment.
Supported by National Natural Science Foundation of China, No. 81260083; and Grants from the Guangxi Natural Science Foundation of China, No. 2014jjAA40237.
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: Hai-Xing Jiang, PhD, Professor, Department of Gastroenterology, The First Affiliated Hospital, Guangxi Medical University, No. 22, Shuang Yong Road, Nanning 530021, Guangxi Zhuang Autonomous Region, China. jihaxi@163.com
Telephone: +86-771-5356725 Fax: +86-771-5356725
Received: May 19, 2014
Peer-review started: May 20, 2014
First decision: June 27, 2014
Revised: August 6, 2014
Accepted: October 15, 2014
Article in press: October 15, 2014
Published online: February 7, 2015
Processing time: 266 Days and 5.5 Hours
Abstract

AIM: To investigate the effect of interleukin (IL)-22 on hepatic fibrosis in mice and the possible mechanism involved.

METHODS: Liver fibrosis was induced in male BALB/c mice by CCl4. Recombinant IL-22 (rmIL-22) was administered intraperitoneally in CCl4-treated mice. Fibrosis was assessed by histology and Masson staining. The activation of hepatic stellate cells (HSCs) was investigated by analysis of α-smooth muscle actin expression. The frequencies of T helper (Th) 22 cells, Th17 cells and Th1 cells, the expression of inflammatory cytokines [IL-22, IL-17A, interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), IL-6, IL-1β] and transcription factors [aryl hydrocarbon receptor (AHR), RAR-related orphan receptor (RORγt), T-bet] mRNA in the liver were investigated. In addition, the plasma levels of IL-22, IL-17A, IFN-γ, TNF-α, IL-6 and IL-1β were evaluated.

RESULTS: Significant elevations in circulating Th22 cells, Th17 cells, Th1 cells, IL-22, IL-17A, and IFN-γ were observed in the hepatic fibrosis group compared with the control group (P < 0.01). Treatment with rmIL-22 in mice with hepatic fibrosis ameliorated the severity of hepatic fibrosis, which was confirmed by lower hepatic fibrosis pathological scores (P < 0.01). RmIL-22 decreased the frequencies of Th22 cells (6.71% ± 0.97% vs 8.09% ± 0.74%, P < 0.01), Th17 cells (4.34% ± 0.37% vs 5.71% ± 0.24%, P < 0.01), Th1 cells (3.09% ± 0.49% vs 4.91% ± 0.73%, P < 0.01), and the levels of IL-22 (56.23 ± 3.08 vs 70.29 ± 3.01, P < 0.01), IL-17A (30.74 ± 2.77 vs 45.68 ± 2.71, P < 0.01), and IFN-γ (74.78 ± 2.61 vs 124.89 ± 2.82, P < 0.01). Down-regulation of IL-22, IL-17A, IFN-γ, TNF-α, IL-6, IL-1β, AHR RORγt, and T-bet gene expression in the liver was observed in the rmIL-22 group (P < 0.01).

CONCLUSION: The frequencies of Th22, Th17 and Th1 cells are elevated in hepatic fibrosis. RmIL-22 can attenuate HSC activation and down-regulate the levels of inflammatory cytokines, thereby ameliorating liver fibrogenesis.

Keywords: T helper 22 cells; T helper 17 cells; T helper 1 cells; Interleukin-22; Hepatic fibrosis

Core tip: T helper (Th)-22 cells are involved in tissue inflammation and immunity. The presence of Th22 cells and the role of interleukin (IL)-22 in hepatic fibrosis have seldom been reported. The present study examined the frequency of Th22 cells, investigated the expression of IL-22, and determined the effects of recombinant IL-22 on hepatic fibrosis in mice. The aim of this preliminary study was to determine the presence of Th22 cells and the functional characteristics of IL-22 in hepatic fibrosis. The frequency of Th22 cells was elevated in mice with hepatic fibrosis. Recombinant IL-22 ameliorated liver fibrogenesis via attenuation of hepatic stellate cell activation and down-regulation of inflammatory cytokines.