These authors contributed equally to this work.
Pathological functions of interleukin-22 in chronic liver inflammation and fibrosis with hepatitis B virus infection by promoting T helper 17 cell recruitment
Article first published online: 1 MAR 2014
© 2014 by the American Association for the Study of Liver Diseases
Volume 59, Issue 4, pages 1331–1342, April 2014
How to Cite
Zhao, J., Zhang, Z., Luan, Y., Zou, Z., Sun, Y., Li, Y., Jin, L., Zhou, C., Fu, J., Gao, B., Fu, Y. and Wang, F.-S. (2014), Pathological functions of interleukin-22 in chronic liver inflammation and fibrosis with hepatitis B virus infection by promoting T helper 17 cell recruitment. Hepatology, 59: 1331–1342. doi: 10.1002/hep.26916
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).
- Issue published online: 24 MAR 2014
- Article first published online: 1 MAR 2014
- Accepted manuscript online: 29 OCT 2013 05:50AM EST
- Manuscript Accepted: 24 OCT 2013
- Manuscript Received: 23 APR 2013
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)