The significance of Osteopontin in development of necrosis, regeneration, fibrosis and carcinogenesis in the liver : Evaluation using osteopontin transgenic mice.

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Osteopontin, an extracellular matrix with RGD sequence, is shown to act as a cytokine essential for initiation of Th1 immune response. Although osteopontin expression is minimal in normal liver, up-regulation of the expression develops in Kupffer cells, macrophages, stellate cells and hepatocytes both in mice and human with liver injury. To clarify the role of osteopontin in the development of liver injury, we made transgenic mice expressing osteopontin exclusively in hepatocytes using the vector containing human serum amyloid P component promoter. In the present study, we evaluated immunological and pathological features of these mice in relation to autoimmune hepatitis.Marked lymphocyte infiltration developed in the periportal areas of the liver later than 12 weeks of age both in male and female mice. These cells were positive for both CD8 and HLA-DR, suggesting that cytotoxic T cells infiltrated in the liver. In these mice, focal necrosis was found in the hepatic lobules. Also, lymp … More hocyte infiltration was observed in the spleen, lung, pancreas and salivary gland, and marked splenomegaly was found later than 24 weeks. Anti-nuclear antibodies in sera assessed by fluorescence immunostaining were positive in 50% of rats between 8 and 48 weeks. Gene expression profile was evaluated in the liver using DNA microarray in mice at 12 weeks. Caplain mRNA expressions were decreased in the liver of transgenic mice compared to non-transgenic mice, while mRNA expressions of metallothionein and glutathione-s-transferase were up-regulated. Serum levels of IFN-γ and IL-10 did not differ between transgenic and non-transgenic mice. The levels increased following intravenous injection of concanavalin-A in both groups. However, IFN-γ level was much more increased in transgenic mice compared to non-transgenic mice, while increase in IL-10 level was less in transgenic mice than in non-transgenic mice. The extent of liver necrosis following concanavalin-A administration was greater in transgenic mice than in non-transgenic mice.Transgenic mice expressing osteopontin in hepatocytes may be a useful model of autoimmune hepatitis, since anti-nuclear antibody was positive in the serum and focal necrosis accompanied by cytotoxic T lymphocyte infiltration developed in the liver. In these mice, mRNA expressions of radical scavenger and detoxifing enzyme were up-regulated prominently in the liver. Also, the mice showed deranged balance in Th1/Th2 cytokine profiles following concanavalin-A administration. Thus, the transgenic mice would be useful tin the study of osteopontin in the development of liver injury in vivo. Less