Attenuated liver progenitor (oval) cell and fibrogenic responses to the choline deficient, ethionine supplemented diet in the BALB/c inbred strain of mice.
OBJECTIVE
Liver regeneration following chronic injury is associated with inflammation, the proliferation of liver progenitor (oval) cells and fibrosis. Previous studies identified interferon-gamma as a key mediator of oval cell proliferation. Interferon-gamma is known to regulate Th1 cell activities during immune challenge. Therefore, we hypothesised that progenitor cell-mediated regeneration is associated with a Th1 immune response.


METHODS
C57Bl/6 (normal Th1 response) and BALB/c mice (deficient in Th1 signalling) were placed on a carcinogenic diet to induce liver injury, progenitor cell proliferation and fibrosis.


RESULTS
Serum transaminases and mortality were elevated in BALB/c mice fed the diet. Proliferation of liver progenitor cells was significantly attenuated in BALB/c animals. The pattern of cytokine expression and inflammation differed between strains. Liver fibrosis and hepatic stellate cell activation were significantly inhibited in BALB/c mice compared to C57Bl/6. In addition, interferon-gamma knockout mice also showed reduced fibrosis compared to wild type. These findings are in contrast to published results, in which interferon-gamma is shown to be anti-fibrogenic.


CONCLUSIONS
Our data demonstrate that the hepatic progenitor cell response to a CDE diet is inhibited in mice lacking Th1 immune signalling and further show that this inhibition is associated with reduced liver fibrosis.
Knight
Belinda
B
School of Medicine and Pharmacology, University of Western Australia, Fremantle Hospital, Alma Rd., Fremantle, WA 6101, Australia. belindat@cyllene.uwa.edu.au
Akhurst
Barbara
B
Matthews
Vance B
VB
Ruddell
Richard G
RG
Ramm
Grant A
GA
Abraham
Lawrence J
LJ
Olynyk
John K
JK
Yeoh
George C
GC
D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D002796:Choline Deficiency / Q000378:metabolism* / Q000473:pathology; D016207:Cytokines / Q000096:biosynthesis; D019587:Dietary Supplements; D005001:Ethionine / Q000008:administration & dosage*; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics; D008103:Liver Cirrhosis / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008115:Liver Regeneration / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013045:Species Specificity; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology; D018417:Th1 Cells / Q000502:physiology
D016207:Cytokines; D007371:Interferon-gamma; D005001:Ethionine