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Prevention of Adenocarcinoma Colon 26-induced Cachexia by Interleukin 10 Gene Transfer¹

Departments of Pharmacology [F. F., N. M., M. A., K. M.] and Molecular Immunology [S. O.], Cancer Research Institute, Department of Hygiene, School of Medicine [A. H.], Kanazawa University, 13-1 Takara-machi, Kanazawa 920, Japan; Third Department of Internal Medicine, School of Medicine, University of Tokushima, 2-50-1, Kuramoto-cho, Tokushima 770, Japan [F. F., S. S.]; Department of Internal Medicine, Clinical Research Center, National Utano Hospital, 8 Ondoyama-cho Narutaki, Ukyo-ku, Kyoto 616, Japan [H. I.]; Biomedical Research Institute, Kureha Chemical Industry, 3-26-2 Hyakunin-cho, Shinjuku-ku, Tokyo 169, Japan [K. H.]; Department of Biology, Pharmaceutical Research Gene Technology, Hoffmann-La Roche Ltd., Basel, Switzerland [H. B.]; Department of Integrated Medicine, Omiya Medical Center, Jichi Medical School, Omiya, Saitama 330, Japan [M. K.]; and Department of Molecular Preventive Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan [K. M.]

A s.c. injection of a mouse colon adenocarcinoma cell line, colon 26 clone 20, induced cachexia, as evidenced by progressive weight loss and severe hypoglycemia. Several lines of evidence indicate that a pro-inflammatory cytokine, interleukin 6 (IL-6), plays a major role, albeit partially, in the establishment of cachexia in this model. Because IL-10 can potently inhibit the production of pro-inflammatory cytokines including IL-6, we evaluated the effects of IL-10 gene transfer on the establishment of cachexia. IL-6 transcript was detected at tumor sites of mice inoculated with parental or control vector transfectant cells, and serum IL-6 levels were markedly increased in these mice. The injection of parental cells into IL-6-deficient mice induced cachexia with elevated serum IL-6 levels comparable to wild-type mice, indicating that tumor cells are a major source of IL-6. The inoculation of IL-10-transfectant cells kept IL-10 mRNA expression at tumor sites and induced the elevation in serum IL-10 levels without affecting the growth rates of colon 26 cells both in vitro and in vivo. However, the implantation with IL-10-transfectant cells reduced the expression of IL-6 mRNA at the tumor sites and the elevation in serum IL-6 levels. Concomitantly, mice inoculated with IL-10-transfectant cells did not exhibit progressive weight loss, a reduction in food intake, or severe hypoglycemia, which was observed in mice inoculated with parental or control vector-transfectant cells. Collectively, these results suggest that IL-10 gene transfer prevented the occurrence of cachexia with a concomitant inhibition of IL-6 production at the tumor sites.

¹ This work was supported in part by the grants from the Ministry of Education, Science, Sports and Culture of Japan, Naito Ryoichi Foundation for Medical Research. The Mochida Memorial Foundation for Medical and Pharmaceutical Research, the Toray Foundation for Research, The Naito Foundation, and The Dr. Shimizu Foundation for the Promotion of Immunology Research Grant for 1995.

² To whom requests for reprints should be addressed.

Received 7/10/96. Accepted 10/29/96.

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