Journal
HEPATOLOGY
Volume 59, Issue 4, Pages 1331-1342Publisher
WILEY-BLACKWELL
DOI: 10.1002/hep.26916
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Funding
- National Natural Science Foundation of China [31170865]
- National Key Basic Research Program of China [2012CB519005, 2009CB522507]
- National Grand Program on Key Infectious Disease [2013ZX10002001-001-003, 2012ZX10002-007-002]
- National Science Fund for Outstanding Young Scholars [81222024]
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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)
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