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CrmA gene expression protects mice against concanavalin-A-induced hepatitis by inhibiting IL-18 secretion and hepatocyte apoptosis

Gene Therapy volume 10, pages 1781–1790 (2003)Cite this article

Abstract

Activated cytotoxic T-cell-mediated hepatocyte apoptosis via Fas/Fas-ligand and perforin/granzyme pathways are believed to involve the model of concanavalin A (ConA)-induced hepatitis. The purpose of the present study is to investigate whether the cytokine response modifier A (crmA) gene effectively inhibits the hepatocyte apoptosis of ConA-induced hepatitis. We examined survival rates, liver pathology, immune histological changes, and cytokine profiles from mice receiving the recombinant adenovirus vectors containing cre and/or crmA genes, transferred to the liver 3 days before ConA injection, and a crmA gene nonexpression control group. Injection of ConA into mice rapidly led to massive hepatocyte apoptosis, and infiltration of leukocytes, especially CD11b+ inflammatory cells. In contrast, liver damage was dramatically reduced in the mice that expressed the crmA gene. However, infiltration by CD4+ cells was not affected. The survival of the mice increased significantly to 100% in the treated group versus the control group. Furthermore, we demonstrated that interleukin (IL)-18 plays an important role in ConA-induced hepatitis, and that crmA expression significantly inhibited IL-18 secretion. Our results showed that the crmA gene effectively inhibits apoptosis induced by ConA hepatitis. This indicates a potential therapeutic usage of crmA for protection from cellular damage due to hepatitis.

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Acknowledgements

We acknowledge Dr Hiromitsu Kimura for his critical comments and useful suggestions. This study was supported by research grants from the Ministry of Health, Labor and Welfare of Japan (12-KO-2, Millennium Project H12-Saisei-016), a Grant-in-Aid (No. 10307030), and a Grant for Organized Research Combination System from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

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Authors and Affiliations

  1. Department of Innovative Surgery, National Research Institute for Child Health and Development, Japan

    M Fujino, M Kawasaki, N Funeshima, Y Kitazawa, S Suzuki & X-K Li

  2. Department of Clinical Genetics and Molecular Medicine, National Center for Child Health and Development, Tokyo, Japan

    M Kosuga & T Okuyama

  3. Laboratory for Developmental Neurobiology, RIKEN Brain Science Institute, Saitama, Japan

    K Okabe, M Hashimoto, H Yaginuma & K Mikoshiba

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Fujino, M., Kawasaki, M., Funeshima, N. et al. CrmA gene expression protects mice against concanavalin-A-induced hepatitis by inhibiting IL-18 secretion and hepatocyte apoptosis. Gene Ther 10, 1781–1790 (2003). https://doi.org/10.1038/sj.gt.3302067

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