PMID- 20578156
OWN - NLM
STAT- MEDLINE
DCOM- 20100719
LR  - 20171116
IS  - 1527-3350 (Electronic)
IS  - 0270-9139 (Linking)
VI  - 52
IP  - 1
DP  - 2010 Jul
TI  - Tumor necrosis factor-like weak inducer of apoptosis is a mitogen for liver 
      progenitor cells.
PG  - 291-302
LID - 10.1002/hep.23663 [doi]
AB  - Liver progenitor cells (LPCs) represent the cell compartment facilitating hepatic 
      regeneration during chronic injury while hepatocyte-mediated repair mechanisms 
      are compromised. LPC proliferation is frequently observed in human chronic liver 
      diseases such as hereditary hemochromatosis, fatty liver disease, and chronic 
      hepatitis. In vivo studies have suggested that a tumor necrosis factor family 
      member, tumor necrosis factor-like weak inducer of apoptosis (TWEAK), is 
      promitotic for LPCs; whether it acts directly is not known. In our murine 
      choline-deficient, ethionine-supplemented (CDE) model of chronic liver injury, 
      TWEAK receptor [fibroblast growth factor-inducible 14 (Fn14)] expression in the 
      whole liver is massively upregulated. We therefore set out to investigate whether 
      TWEAK/Fn14 signaling promotes the regenerative response in CDE-induced chronic 
      liver injury by mitotic stimulation of LPCs. Fn14 knockout (KO) mice showed 
      significantly reduced LPC numbers and attenuated inflammation and cytokine 
      production after 2 weeks of CDE feeding. The close association between LPC 
      proliferation and activation of hepatic stellate cells in chronic liver injury 
      prompted us to investigate whether fibrogenesis was also modulated in Fn14 KO 
      animals. Collagen deposition and expression of key fibrogenesis mediators were 
      reduced after 2 weeks of injury, and this correlated with LPC numbers. 
      Furthermore, the injection of 2-week-CDE-treated wildtype animals with TWEAK led 
      to increased proliferation of nonparenchymal pan cytokeratin-positive cells. 
      Stimulation of an Fn14-positive LPC line with TWEAK led to nuclear factor kappa 
      light chain enhancer of activated B cells (NFkappaB) activation and 
      dose-dependent proliferation, which was diminished after targeting of the p50 
      NFkappaB subunit by RNA interference. CONCLUSION: TWEAK acts directly and 
      stimulates LPC mitosis in an Fn14-dependent and NFkappaB-dependent fashion, and 
      signaling via this pathway mediates the LPC response to CDE-induced injury and 
      regeneration.
FAU - Tirnitz-Parker, Janina E E
AU  - Tirnitz-Parker JE
AD  - School of Medicine and Pharmacology, University of Western Australia, Fremantle, 
      Australia. J.Tirnitz-Parker@curtin.edu.au
FAU - Viebahn, Cornelia S
AU  - Viebahn CS
FAU - Jakubowski, Aniela
AU  - Jakubowski A
FAU - Klopcic, Borut R S
AU  - Klopcic BR
FAU - Olynyk, John K
AU  - Olynyk JK
FAU - Yeoh, George C T
AU  - Yeoh GC
FAU - Knight, Belinda
AU  - Knight B
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Hepatology
JT  - Hepatology (Baltimore, Md.)
JID - 8302946
RN  - 0 (Cytokine TWEAK)
RN  - 0 (Mitogens)
RN  - 0 (NF-kappa B)
RN  - 0 (Receptors, Tumor Necrosis Factor)
RN  - 0 (Recombinant Proteins)
RN  - 0 (TNFRSF12A protein, human)
RN  - 0 (TWEAK Receptor)
RN  - 0 (Tnfrsf12a protein, mouse)
RN  - 0 (Tnfsf12 protein, mouse)
RN  - 0 (Tumor Necrosis Factors)
RN  - 9007-34-5 (Collagen)
RN  - WX1BN24WZT (Ethionine)
SB  - IM
CIN - Hepatology. 2010 Jul;52(1):13-5. PMID: 20578125
MH  - Animals
MH  - Cell Proliferation
MH  - Choline Deficiency/metabolism
MH  - Collagen/metabolism
MH  - Cytokine TWEAK
MH  - Ethionine/pharmacology
MH  - Liver/drug effects/injuries
MH  - *Liver Regeneration
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Mitogens/pharmacology
MH  - *Mitosis
MH  - NF-kappa B/agonists/genetics/metabolism
MH  - Receptors, Tumor Necrosis Factor/genetics
MH  - Recombinant Proteins/pharmacology
MH  - Stem Cells/drug effects/*physiology
MH  - TWEAK Receptor
MH  - Tumor Necrosis Factors/pharmacology/*physiology
EDAT- 2010/06/26 06:00
MHDA- 2010/07/20 06:00
CRDT- 2010/06/26 06:00
PHST- 2010/06/26 06:00 [entrez]
PHST- 2010/06/26 06:00 [pubmed]
PHST- 2010/07/20 06:00 [medline]
AID - 10.1002/hep.23663 [doi]
PST - ppublish
SO  - Hepatology. 2010 Jul;52(1):291-302. doi: 10.1002/hep.23663.