Z Gastroenterol 2012; 50 - P1_59
DOI: 10.1055/s-0031-1295791

IFN-gamma inhibits hepatic progenitor cell activation in patients with chronic hepatitis B and in mice

H Weng 1, S Radaeva 2, D Feng 2, Y Gao 2, Y Liu 1, Q Li 1, H Shen 1, R Müllenbach 3, T Huang 4, JL Chen 5, V Zimmer 3, F Lammert 3, PR Mertens 6, S Zakhari 2, WM Cai 7, S Dooley 1, B Gao 2
  • 1II. Medizinische Klinik Universtitätsklinikum Mannheim, Universitäts Heidelberg, Mannheim, Germany
  • 2Laboratory of Liver Diseases, Division of Metabolism and Health Effects, National Institute on Alcohol Abuse and Alcoholism, NIH, USA, Bethesda
  • 3Department of Medicine II, Saarland University Hospital, Saarland University, Homburg
  • 4Department of Cardiac Vascular Medicine, Li Hui Li Hospital, Medical School, Ningbo University, Ningbo, China
  • 5Department of Pathology, First Hospital of Jiaxing, College of Jiaxing, Jiaxing, China
  • 6Department of Nephrology and Hypertension, Otto-von-Guericke-University, Magdeburg
  • 7Institute of Infectious Diseases, First Affiliated Hospital, Medical School, Zhejiang University, Hangzhou, China

Aims: Hepatic progenitor cells (HPCs) are crucial in hepatic regeneration and liver remodelling. A correlation of HPC activation during periportal fibrosis in HCV- and NASH-associated liver diseases suggests a role in fibrogenesis. IFN-γ is well recognized as fibrotic inhibitor and also may participate in regulation of HPC activation, although current results are controversial. To get further insight, we studied HPC activation in HBV infected patients and 3,5-diethoxycarbonyl–1,4-dihydrocollidine (DDC) treated mice. Methods: Human HPCs and mouse oval cells (HPCs in rodents) were quantified by cytokeratin–19 (CK19) immunostaining in chronic HBV infected patients and DDC treated wild-type and four kinds of IFN-γ-signaling associated knockout mice (IFN-γ-, IFN-γ receptor-, STAT- and interferon regulator factor (IRF)–1). Results: The CK19 staining score significantly correlates with inflammatory grade (r=0.61, P<0.001) and fibrotic stage (r=0.61, P<0.001) in 110 patients with chronic HBV infection. Nine months IFN-γ treatment decreased HPC numbers concomitant with reduced inflammation and fibrosis in 13/18 such HBV patients. Similarly, 2 weeks IFN-γ treatment remarkably decreased oval cell activation in DDC treated mice, whereas their number was significantly increased in all four knock out models with disrupted IFN-γ signaling. Co-staining for CK19 and BrdU revealed significant increased oval cell proliferation in STAT1- and IRF–1 knockout mice compared with wild-type mice. In vitro, IFN-γ incubation decreased BrdU marked proliferation of wild-type mouse primary oval cells, however, IFN- γ loss this effect in oval cells isolated from STAT1- or IRF–1 knockout mice. In parallel with upregulated oval cell expansion, DDC-mediated inflammatory and fibrotic reactions were remarkably enhanced in all mice with disrupted IFN-γ signaling. Conclusions: Besides its anti-fibrotic role, IFN-γ negatively regulates HPC/oval cell activation in chronic liver damage.

fibrosis - Stat