title: Pathological Roles of Interleukin-22 in the Development of Recurrent Hepatitis C after Liver Transplantation.
abstract: The aim of this study was to longitudinally evaluate and analyze the role of interleukin-22-producing CD4 positive cells (IL-22) in the pathogenesis of Hepatitis C Virus recurrence after Orthotopic Liver Transplantation (HCV-OLT).
  
  
  
  15 HCV-OLT, 15 age- and gender- matched non-HCV post-OLT (OLT) and 15 hepatitis C virus infected (HCV) patients were enrolled into our study from the liver transplantation and research center at Beijing 302 Hospital. We determined the frequencies of IL-22 using flow cytometry and expression of IL-22 mRNA using PCR in peripheral blood and liver tissue. We also divided HCV-OLT patients into rapid fibrosis progression (RFP) and slow fibrosis progression (SFP), examined IL-22 cells and analyzed the correlations between IL-22 frequencies and liver injury, fibrosis and clinical parameters. Moreover, we investigated the role of IL-22 in Human Hepatic Stellate Cells (HSCs).
  
  
  
  The levels of serum IL-22, frequencies of IL-22 producing cells in peripheral blood mononuclear cells, and expression of IL-22 mRNA and protein in the liver in the HCV-OLT group were significantly higher than that in the HCV and OLT groups. Furthermore, eight (53.3%) patients developed RFP after two years; another three patients were diagnosed liver cirrhosis. The frequencies of IL-22 were much higher in RFP compared with SFP, while no significant difference existed between OLT and SFP. Intrahepatic IL-22 positive cells were located in fibrotic areas and significantly correlated with α-smooth muscle actin (α-SMA) and fibrosis staging scores, not with grading scores and HCRVNA. In vitro, IL-22 administration prevented HSCs apoptosis, promoted HSCs proliferation and activation, up-regulated the expression of HSC-sourced growth factors including α-SMA, TGF-β and TIMP-1, and increased the production of liver fibrosis markers including laminin, hyaluronic acid and collagen type IV.
  
  
  
  Peripheral and intrahepatic IL-22 is up-regulated and plays a pathological role in exacerbating liver fibrosis by activating HSCs in HCV-OLT patients, which may predict RFP and serve as an attractive target for anti-fibrotic therapy.
authors.affiliation: Liver Transplantation and Research Center, 302 Military Hospital, Beijing, China.|Department of Infectious Diseases, Medical School of Chinese PLA, Beijing, China.
authors.forename: Yinjie
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Liver Transplantation and Research Center, 302 Military Hospital, Beijing, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Ren
authors.affiliation: Liver Cirrhosis and Research Center, 302 Military Hospital, Beijing, China.
authors.forename: Fanping
authors.initials: F
authors.lastname: Meng
authors.affiliation: Liver Transplantation and Research Center, 302 Military Hospital, Beijing, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Li
authors.affiliation: California Pacific Medical Center, San Francisco, California, United States of America.|University of California at Davis school of medicine, Sacramento, California, United States of America.
authors.forename: Eddie
authors.initials: E
authors.lastname: Cheung
authors.affiliation: Liver Cirrhosis and Research Center, 302 Military Hospital, Beijing, China.
authors.forename: Hanwei
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Pathology and Hepatology, 302 Military Hospital, Beijing, China.
authors.forename: Jingmin
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Liver Transplantation and Research Center, 302 Military Hospital, Beijing, China.
authors.forename: Hongling
authors.initials: H
authors.lastname: Liu
authors.affiliation: Liver Transplantation and Research Center, 302 Military Hospital, Beijing, China.
authors.forename: Zhenwen
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Liver Transplantation and Research Center, 302 Military Hospital, Beijing, China.
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
mesh_terms: D000199:Actins / Q000235:genetics / Q000276:immunology; D000328:Adult; D024141:Collagen Type IV / Q000235:genetics / Q000276:immunology; D018450:Disease Progression; D005260:Female; D015870:Gene Expression; D016174:Hepacivirus / Q000276:immunology / Q000472:pathogenicity; D055166:Hepatic Stellate Cells / Q000276:immunology / Q000473:pathology* / Q000821:virology; D019698:Hepatitis C, Chronic / Q000235:genetics / Q000276:immunology / Q000473:pathology* / Q000821:virology; D006801:Humans; D006820:Hyaluronic Acid / Q000096:biosynthesis / Q000276:immunology; D007378:Interleukins / Q000235:genetics* / Q000276:immunology; D007797:Laminin / Q000235:genetics / Q000276:immunology; D008099:Liver / Q000276:immunology / Q000473:pathology* / Q000601:surgery / Q000821:virology; D008103:Liver Cirrhosis / Q000235:genetics / Q000276:immunology / Q000473:pathology* / Q000821:virology; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000235:genetics / Q000276:immunology; D012008:Recurrence; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology; D019562:Viral Load / Q000276:immunology; D000097043:Interleukin-22
chemical_list: D000199:Actins; D024141:Collagen Type IV; D006820:Hyaluronic Acid; D007378:Interleukins; D007797:Laminin; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D016212:Transforming Growth Factor beta; D000097043:Interleukin-22; C541116:ACTA2 protein, human