Transgenic mice expressing osteopontin in hepatocytes as a model of autoimmune hepatitis.
Osteopontin, a crucial factor for Th1 immune response, is expressed in stellate cells and macrophages activated in injured liver. To clarify the role of osteopontin in inflammatory changes in the liver, we attempted to establish transgenic mice expressing osteopontin in hepatocytes. Mouse osteopontin cDNA, cloned from concanavalin-A-stimulated spleen cells in C57BL/6 mice, was constructed into the vector containing serum amyloid-P component promoter. This construction was microinjected into fertilized eggs of C57BL/6 mice, and 4 lines of the transgenic mice were obtained. Western blotting and immunohistochemistry revealed that osteopontin was expressed in hepatocytes, but not in non-parenchymal cells, in the transgenic mice. The mean osteopontin concentrations in the liver and plasma in the mice were 13 and 2.6 times higher than those in negative littermates. Antinuclear antibody was positive in the plasma in 50% of the transgenic mice. In the transgenic mice later than 12 weeks of age, mononuclear cell infiltration in the liver developed, and these cells were positive for CD8 and HLA-DR. Plasma ALT activity was increased with focal necrosis in hepatic lobules in the transgenic mice later than 24 weeks of age. The transgenic mice expressing osteopontin in hepatocytes may be useful as a model of autoimmune hepatitis.
Mochida
Satoshi
S
Division of Gastroenterology and Hepatology (The Third Department of Internal Medicine), Saitama Medical School, Saitama, Japan.
Yoshimoto
Takayuki
T
Mimura
Sumie
S
Inao
Mie
M
Matsui
Atsushi
A
Ohno
Akihiko
A
Koh
HeaSaeng
H
Saitoh
Eiko
E
Nagoshi
Sumiko
S
Fujiwara
Kenji
K
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D005796:Genes; D005822:Genetic Vectors; D019693:Hepatitis, Autoimmune / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D022781:Hepatocytes / Q000276:immunology* / Q000378:metabolism; D007150:Immunohistochemistry; D008099:Liver / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009336:Necrosis; D053495:Osteopontin; D000683:Serum Amyloid P-Component / Q000235:genetics; D012795:Sialoglycoproteins / Q000096:biosynthesis / Q000097:blood / Q000235:genetics / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014018:Tissue Distribution
D000683:Serum Amyloid P-Component; D012795:Sialoglycoproteins; C506896:Spp1 protein, mouse; D053495:Osteopontin; D000410:Alanine Transaminase