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

Juanjuan Zhao, Zheng Zhang, Yan Luan, Zhengsheng Zou, Yanling Sun, Yonggang Li, Lei Jin, Chunbao Zhou, Junliang Fu, Bin Gao, Yangxin Fu, Fu Sheng Wang

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)1331-1342
Number of pages12
JournalHepatology
Volume59
Issue number4
DOIs
StatePublished - Jan 1 2014

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Th17 Cells
Virus Diseases
Hepatitis B virus
Liver Cirrhosis
Inflammation
Hepatic Stellate Cells
Liver
Chemotaxis
Chemokines
Transgenic Mice
Chemokine CXCL10
Ligands
interleukin-22
CXC Chemokines
Chemokine Receptors
Microarray Analysis
Hepatocytes
Healthy Volunteers
Immunohistochemistry
T-Lymphocytes

ASJC Scopus subject areas

  • Hepatology

Cite this

Pathological functions of interleukin-22 in chronic liver inflammation and fibrosis with hepatitis B virus infection by promoting T helper 17 cell recruitment. / Zhao, Juanjuan; Zhang, Zheng; Luan, Yan; Zou, Zhengsheng; Sun, Yanling; Li, Yonggang; Jin, Lei; Zhou, Chunbao; Fu, Junliang; Gao, Bin; Fu, Yangxin; Wang, Fu Sheng.

In: Hepatology, Vol. 59, No. 4, 01.01.2014, p. 1331-1342.

Research output: Contribution to journalArticle

Zhao, Juanjuan ; Zhang, Zheng ; Luan, Yan ; Zou, Zhengsheng ; Sun, Yanling ; Li, Yonggang ; Jin, Lei ; Zhou, Chunbao ; Fu, Junliang ; Gao, Bin ; Fu, Yangxin ; Wang, Fu Sheng. / Pathological functions of interleukin-22 in chronic liver inflammation and fibrosis with hepatitis B virus infection by promoting T helper 17 cell recruitment. In: Hepatology. 2014 ; Vol. 59, No. 4. pp. 1331-1342.
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AU - Zhang, Zheng

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AU - Zou, Zhengsheng

AU - Sun, Yanling

AU - Li, Yonggang

AU - Jin, Lei

AU - Zhou, Chunbao

AU - Fu, Junliang

AU - Gao, Bin

AU - Fu, Yangxin

AU - Wang, Fu Sheng

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N2 - 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.

AB - 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.

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