PMID- 23747755
OWN - NLM
STAT- MEDLINE
DCOM- 20140602
LR  - 20211021
IS  - 1600-0641 (Electronic)
IS  - 0168-8278 (Print)
IS  - 0168-8278 (Linking)
VI  - 59
IP  - 4
DP  - 2013 Oct
TI  - IFN-gamma inhibits liver progenitor cell proliferation in HBV-infected patients and 
      in 3,5-diethoxycarbonyl-1,4-dihydrocollidine diet-fed mice.
PG  - 738-45
LID - S0168-8278(13)00374-7 [pii]
LID - 10.1016/j.jhep.2013.05.041 [doi]
AB  - 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 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-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.
CI  - Copyright (c) 2013 European Association for the Study of the Liver. Published by 
      Elsevier B.V. All rights reserved.
FAU - Weng, Hong-lei
AU  - Weng HL
AD  - Department of Medicine II, Section Molecular Hepatology, Medical Faculty 
      Mannheim, Heidelberg University, Mannheim, Germany.
FAU - Feng, De-chun
AU  - Feng DC
FAU - Radaeva, Svetlana
AU  - Radaeva S
FAU - Kong, Xiao-ni
AU  - Kong XN
FAU - Wang, Lei
AU  - Wang L
FAU - Liu, Yan
AU  - Liu Y
FAU - Li, Qi
AU  - Li Q
FAU - Shen, Hong
AU  - Shen H
FAU - Gao, Yun-peng
AU  - Gao YP
FAU - Mullenbach, Roman
AU  - Mullenbach R
FAU - Munker, Stefan
AU  - Munker S
FAU - Huang, Tong
AU  - Huang T
FAU - Chen, Jia-lin
AU  - Chen JL
FAU - Zimmer, Vincent
AU  - Zimmer V
FAU - Lammert, Frank
AU  - Lammert F
FAU - Mertens, Peter R
AU  - Mertens PR
FAU - Cai, Wei-min
AU  - Cai WM
FAU - Dooley, Steven
AU  - Dooley S
FAU - Gao, Bin
AU  - Gao B
LA  - eng
GR  - Z99 AA999999/ImNIH/Intramural NIH HHS/United States
GR  - ZIA AA000368-11/ImNIH/Intramural NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130604
PL  - Netherlands
TA  - J Hepatol
JT  - Journal of hepatology
JID - 8503886
RN  - 0 (3,5-diethoxycarbonyl-1,4-dihydrocollidine)
RN  - 0 (Pyridines)
RN  - 82115-62-6 (Interferon-gamma)
SB  - IM
MH  - Adult Stem Cells/*cytology/drug effects/physiology
MH  - Animals
MH  - Cell Line
MH  - Cell Proliferation/drug effects
MH  - Hepatic Stellate Cells/drug effects/pathology/physiology
MH  - Hepatitis B, Chronic/*pathology/physiopathology
MH  - Hepatocytes/*cytology/drug effects/physiology
MH  - Humans
MH  - Interferon-gamma/deficiency/pharmacology/*physiology
MH  - Liver Cirrhosis/pathology/physiopathology/prevention & control
MH  - Macrophage Activation/drug effects
MH  - Mice
MH  - Mice, Knockout
MH  - Pyridines/administration & dosage/toxicity
MH  - Signal Transduction/drug effects
PMC - PMC3779479
MID - NIHMS513041
OTO - NOTNLM
OT  - 3,5-diethoxycarbonyl-1,4-dihydrocollidine
OT  - ALT
OT  - BMOL
OT  - BrdU
OT  - CCl(4)
OT  - CDE
OT  - CK19
OT  - CK7
OT  - Cytokeratin-19
OT  - Cytokeratin-7
OT  - DDC
OT  - DR
OT  - ECM
OT  - HSC
OT  - Hepatic stellate cells
OT  - IHC
OT  - IHLC
OT  - IRF-1
OT  - LPC
OT  - LPS
OT  - MPK
OT  - Macrophages
OT  - NK cell
OT  - NKT cell
OT  - PCNA
OT  - STAT1
OT  - T helper 1
OT  - Th1
OT  - alanine aminotransferase
OT  - bipotential murine oval liver
OT  - bromodeoxyuridine
OT  - carbon tetrachloride
OT  - choline deficient, ethionine supplemented diet
OT  - cytokeratin-19
OT  - cytokeratin-7
OT  - ductular reaction
OT  - extracellular matrix
OT  - hepatic stellate cell
OT  - immunohistochemistry
OT  - interferon regulator factor-1
OT  - intermediate hepatocyte-like cell
OT  - lipopolysaccharide
OT  - liver progenitor cells
OT  - muscle pyruvate kinase
OT  - natural killer T cell
OT  - natural killer cell
OT  - proliferating cell nuclear antigen
OT  - signal transducer and activator of transcription 1
OT  - alpha-SMA
OT  - alpha-smooth muscle actin
COIS- The authors have no conflicting financial interests.
EDAT- 2013/06/12 06:00
MHDA- 2014/06/03 06:00
PMCR- 2014/10/01
CRDT- 2013/06/11 06:00
PHST- 2013/02/25 00:00 [received]
PHST- 2013/05/22 00:00 [revised]
PHST- 2013/05/24 00:00 [accepted]
PHST- 2013/06/11 06:00 [entrez]
PHST- 2013/06/12 06:00 [pubmed]
PHST- 2014/06/03 06:00 [medline]
PHST- 2014/10/01 00:00 [pmc-release]
AID - S0168-8278(13)00374-7 [pii]
AID - 10.1016/j.jhep.2013.05.041 [doi]
PST - ppublish
SO  - J Hepatol. 2013 Oct;59(4):738-45. doi: 10.1016/j.jhep.2013.05.041. Epub 2013 Jun 
      4.