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

Abstract

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)-γ, 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 choline-deficient, 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-γ treatment decreased LPC numbers, inflammation, and fibrosis in these HBV-infected patients. Similarly, a two-week IFN-γ treatment also decreased LPC activation in DDC-treated mice. Disruption of IFN-γ 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-γ did not increase, but rather slightly reduced LPC proliferation in CDE-fed mice. In vitro, IFN-γ 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-γ can indirectly promote LPC proliferation via the activation of macrophages but attenuate it via the inhibition of hepatic stellate cells.

Conclusions: IFN-γ 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.

Keywords: 3,5-diethoxycarbonyl-1,4-dihydrocollidine; ALT; BMOL; BrdU; CCl(4); CDE; CK19; CK7; Cytokeratin-19; Cytokeratin-7; DDC; DR; ECM; HSC; Hepatic stellate cells; IHC; IHLC; IRF-1; LPC; LPS; MPK; Macrophages; NK cell; NKT cell; PCNA; STAT1; T helper 1; Th1; alanine aminotransferase; bipotential murine oval liver; bromodeoxyuridine; carbon tetrachloride; choline deficient, ethionine supplemented diet; cytokeratin-19; cytokeratin-7; ductular reaction; extracellular matrix; hepatic stellate cell; immunohistochemistry; interferon regulator factor-1; intermediate hepatocyte-like cell; lipopolysaccharide; liver progenitor cells; muscle pyruvate kinase; natural killer T cell; natural killer cell; proliferating cell nuclear antigen; signal transducer and activator of transcription 1; α-SMA; α-smooth muscle actin.