IFN-γ inhibits liver progenitor cell proliferation in HBV-infected patients and in 3,5-diethoxycarbonyl-1,4-dihydrocollidine diet-fed mice

JOURNAL OF HEPATOLOGY

卷:59

Article

Weng, Hong-lei¹  Feng, De-chun²  Radaeva, Svetlana²  Kong, Xiao-ni²  Wang, Lei²  Liu, Yan¹  Li, Qi¹  Shen, Hong¹  Gao, Yun-peng²  Muellenbach, Roman^1,3  Munker, Stefan¹  Huang, Tong⁴  Chen, Jia-lin⁵  Zimmer, Vincent³  Lammert, Frank³  Mertens, Peter R.⁶  Cai, Wei-min⁷  Dooley, Steven¹  Gao, Bin² 

[1] Heidelberg Univ, Med Fac Mannheim, Dept Med 2, Sect Mol Hepatol, Mannheim, Germany

[2] NIAAA, Lab Liver Dis, NIH, Bethesda, MD 20892 USA

[3] Univ Saarland, Saarland Univ Hosp, Dept Med 2, Homburg, Germany

[4] Ningbo Univ, Sch Med, Li Hui Li Hosp, Dept Cardiac Vasc Med, Ningbo 315211, Zhejiang, Peoples R China

[5] First Hosp Jiaxing, Coll Jiaxing, Dept Pathol, Jiaxing, Peoples R China

[6] Otto Von Guericke Univ, Dept Hypertens & Nephrol, Magdeburg, Germany

[7] Zhejiang Univ, Sch Med, Affiliated Hosp 1, Inst Infect Dis, Hangzhou 310003, Zhejiang, Peoples R China

关键词: Cytokeratin-19;    Cytokeratin-7;    STAT1;    IRF-1;    Hepatic stellate cells;    Macrophages;   

DOI  :  10.1016/j.jhep.2013.05.041

来源: Elsevier

【 摘 要 】

Background & Aims: Proliferation of liver progenitor cells (LPCs) is associated with inflammation and fibrosis in chronic liver diseases. However, how inflammation and fibrosis affect LPCs remains obscure. Methods: We examined the role of interferon (IFN)-gamma, an important pro-inflammatory and anti-fibrotic cytokine, in LPC expansion in HBV-infected patients and in mice challenged with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-or cholinedeficient, ethionine-supplemented (CDE) diet as well as in primary LPCs and LPC cell line. Results: The CK19 staining scores correlated with inflammation and fibrosis grades in the livers from 110 HBV-infected patients. Nine-month IFN-gamma treatment decreased LPC numbers, inflammation, and fibrosis in these HBV-infected patients. Similarly, a two-week IFN-gamma treatment also decreased LPC activation in DDC-treated mice. Disruption of IFN-gamma or its signaling components (e.g., IFNGR, STAT1, and IRF-1) increased LPC proliferation and liver fibrosis in DDC-fed mice. In contrast, deletion of IFN-gamma did not increase, but rather slightly reduced LPC proliferation in CDE-fed mice. In vitro, IFN-gamma attenuated proliferation of the LPC cell line BMOL and of primary LPCs from wild type mice, but not STAT1(-/-) or IRF-1(-/-) mice. Furthermore, co-culture assays suggest that IFN-gamma can indirectly promote LPC proliferation via the activation of macrophages but attenuate it via the inhibition of hepatic stellate cells. Conclusions: IFN-gamma inhibits LPC expansion via the direct inhibition of LPC proliferation and indirect attenuation of liver fibrosis in the DDC model, but it may also enhance LPC expansion via the promotion of inflammation in the CDE model; thereby playing dual roles in regulating LPC proliferation in vivo. Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver.

【 授权许可】

Free