Pathological functions of interleukin-22 in chronic liver... : Hepatology (original) (raw)

Viral Hepatitis

Pathological functions of interleukin-22 in chronic liver inflammation and fibrosis with hepatitis B virus infection by promoting T helper 17 cell recruitment

Zhao, Juanjuan1; Zhang, Zheng1; Luan, Yan2; Zou, Zhengsheng3; Sun, Yanling4; Li, Yonggang5; Jin, Lei1; Zhou, Chunbao1; Fu, Junliang1; Gao, Bin6; Fu, Yangxin2; Wang, Fu-Sheng1

1_Research Center for Biological Therapy, Beijing 302 Hospital, Beijing, China_

2_Chinese Academy of Sciences Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China_

3_Center for Non-infectious Liver Diseases, Beijing 302 Hospital, Beijing, China_

4_Research Center for Liver Transplantation, Beijing 302 Hospital, Beijing, China_

5_Integrative Medicine Center, Beijing 302 Hospital, Beijing, China_

6_Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA,_

Received 23 April 2013; Accepted 24 October 2013

Address reprint requests to: Fu-Sheng Wang, Ph.D., M.D., Research Center for Biological Therapy, Beijing 302 Hospital, 100 Western 4th Ring Middle Road, Beijing 100039, China. E-mail: [email protected]; fax: +86-010-63879735.

These authors contributed equally to this work.

Potential conflict of interest: Nothing to report.

This work was supported by the The National Natural Science Foundation of China (31170865), the National Key Basic Research Program of China (2012CB519005 and 2009CB522507), the National Grand Program on Key Infectious Disease (2013ZX10002001-001-003 and 2012ZX10002-007-002), and the National Science Fund for Outstanding Young Scholars (81222024).

Additional Supporting Information may be found in the online version of this article.

Abstract

It is well established that interleukin (IL)-22 has hepatoprotective and antifibrotic functions in acute liver injury models; however, its function in patients with liver fibrosis and liver cirrhosis (LC) remains obscure. In the current study, we demonstrated that expression of numerous IL-22 pathway-associated genes was significantly up-regulated in hepatitis B virus (HBV)-infected liver tissues, compared to normal controls, through microarray analysis. In agreement with these findings, liver-infiltrating IL-22+ cells were largely increased in HBV-infected patients with LC, compared to those without LC or healthy subjects, and were positively associated with liver fibrosis staging scores. Immunohistochemistry and flow cytometric analyses revealed that IL-22 was produced by multiple intrahepatic immune cells and, preferentially, by T-helper (Th) 17 cells in LC patients. In an HBV transgenic (Tg) mouse model of T-cell-mediated chronic liver inflammation and fibrosis, blockade of IL-22 attenuated hepatic expression of chemokine (C-X-C motif) ligand 10 and chemokine (C-C motif) ligand 20 (CCL20) and subsequently reduced Th17 recruitment and liver inflammation and fibrosis progression. In vitro treatment with IL-22 stimulated hepatic stellate cells (HSCs) to secrete several chemokines and subsequently promoted Th17 cell chemotaxis. Blocking C-X-C chemokine receptor type 3 or CCL20 reduced Th17 cell chemotaxis by IL-22-treated HSCs. Conclusions: IL-22 plays a pathological role in exacerbating chronic liver inflammation and fibrosis by recruiting hepatic Th17 cells in HBV-infected patients and HBV Tg mice. (HEPATOLOGY 2014;59:1331-1342)