Fulminant hepatitis by Fas-ligand expression in MRL-lpr/lpr mice grafted with Fas-positive livers and wild-type mice with Fas-mutant livers.
BACKGROUND
Fulminant hepatitis in mice could be induced by gene-transfection of Fas ligand (FasL). However, the mechanisms of this event still remain controversial as to whether it is mediated by direct Fas/FasL interaction and/or neutrophil migration. To investigate the role of exogenous FasL-expression, we established a simple but clear mouse model on which we performed liver transplantation between Fas-mutant mice (MRL-lpr/lpr) and wild-type mice (MRL+/+).


METHODS
The controls were nontransplanted wild-type (group 1) and MRL-lpr/lpr (group 2) mice. We obtained recipients with a Fas defect only in the liver (group 3; MRL-lpr/lpr liver graft in wild-type mice) and Fas-defected recipients with Fas-positive livers (group 4; wild-type graft in MRL-lpr/lpr). We successfully expressed FasL in the liver by cotransfection of two types of adenoviral vectors, AxCALNFasL and AxCANCre, with a Cre-loxP switching system.


RESULTS
FasL-expression in the livers in groups 3 and 4 resulted in animal death due to fulminant hepatitis within 48 hr after administration of the vectors. We obtained similar findings in group 1, whereas the mice in group 2 survived without any evidence of hepatitis. Immune staining revealed a marked infiltration of CD11b-positive cells in group 1 and group 3. Despite the number of apoptotic cells, a few infiltration of CD11b-positive cells were seen in group 4. We observed no remarkable findings in the FasL-expressed livers in group 2.


CONCLUSIONS
The results indicated that exogenous FasL-expression induces hepatocyte apoptosis both by direct interaction with Fas and by recruiting Fas-positive inflammatory cells. These findings are important for generating a new strategy to prevent hepatitis as well as for understanding the role of the Fas/FasL interaction in the pathophysiology of hepatitis.
Department of Experimental Surgery and Bioengineering, National Children's Medical Research Center, Tokyo, Japan.
X K
XK
Li
M
M
Fujino
A
A
Sugioka
M
M
Morita
T
T
Okuyama
L
L
Guo
N
N
Funeshima
H
H
Kimura
S
S
Enosawa
H
H
Amemiya
S
S
Suzuki
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects; D053222:Fas Ligand Protein; D015870:Gene Expression; D005822:Genetic Vectors; D006505:Hepatitis / Q000209:etiology*; D022781:Hepatocytes / Q000166:cytology; D020287:In Situ Nick-End Labeling; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D023421:Models, Animal
D000906:Antibodies; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins