International Immunology, Vol. 11, No. 9, 1491-1500,
September 1999
© 1999 Japanese Society for Immunology
Immunopathogenesis of hepatic fibrosis in chronic liver injury induced by repeatedly administered concanavalin A
First Department of Internal Medicine and
1 Department of Laboratory Medicine,Gifu University School of Medicine, 40 Tsukasa-machi, Gifu 500-8705, Japan
2 First Department of Internal Medicine, Aichi Medical University, Nagakute-cho, Aichi district, Aichi 480-1100, Japan
Correspondence to: K. Ando
Liver fibrosis is commonly observed in chronic liver disease. However, the immunological mechanisms underlying hepatic fibrosis due to chronic inflammation are not well defined, mainly because suitable experimental models have not been established. We have found that weekly i.v. administration of concanavalin A (Con A) in BALB/c mice brought about a striking alanine aminotransferase increase, resulting in piecemeal necrosis with bridging fibrosis in the parenchyma. Using this fibrosis model, we demonstrated the kinetics of cytokine mRNA expression in liver. Transforming growth factor (TGF)-ß1, TGF-
, basic fibroblast growth factor (bFGF) and hepatocyte growth factor mRNAs were up-regulated after each Con A administration. Furthermore, either anti-IFN-
, anti-tumor necrosis factor (TNF)- or anti-TGF-ß mAb given together with Con A markedly inhibited the development of hepatic fibrosis. Treatment with either anti-IFN- or anti-TNF- mAb also completely prevented hepatic injury; in contrast, treatment with anti-TGF-ß mAb did not. The treatment with anti-TGF-ß mAb did not affect the levels of hepatic mRNAs for either IFN- or TNF- after Con A injection. Treatment with either anti-IFN- or anti-TNF- did not affect the expression levels of TGF-ß in the liver. In conclusion, the continuous presence of both severe liver damage and up-regulation of TGF-ß synthesis is necessary to induce hepatic fibrosis in this model.
Keywords: concanavalin A, hepatic fibrosis, hepatitis, immunology, in vivo animal model, transforming growth factor-ß
Transmitting editor: K. Okumura
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