Fulminant hepatitis by Fas-ligand expression in MRL-lpr/lpr mice grafted with Fas-positive livers and wild-type mice with Fas-mutant livers

Xiao Kang Li, Masayuki Fujino, Atsushi Sugioka, Miwa Morita, Torayuki Okuyama, Lei Guo, Naoko Funeshima, Hiromitsu Kimura, Shin Enosawa, Hiroshi Amemiya, Seiichi Suzuki

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)

Abstract

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-mutent 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 Ax-CANCre, 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. Conclusion. 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.

Original languageEnglish
Pages (from-to)503-508
Number of pages6
JournalTransplantation
Volume71
Issue number4
DOIs
Publication statusPublished - 27-02-2001

All Science Journal Classification (ASJC) codes

  • Transplantation

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