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. 1995 Nov;41(6):355–362. doi: 10.1007/BF01526555

Restoration of interleukin-2 production in tumor-bearing rats through reducing tumor-derived transforming growth factor β by treatment with bleomycin

Lan Yuan 1, Yasuhiro Kuramitsu 1, Yongqin Li 1, Masanobu Kobayashi 1, Masuo Hosokawa 1,✉
PMCID: PMC11037597  PMID: 8635193

Abstract

We studied mechanisms of immunosuppression caused by tumor-derived transforming growth factor-ß (TGFß) and restoration of the immune response by treatment with bleomycin in rats bearing KDH-8 hepatoma. Interleukin-2 (IL-2) production from splenocytes of KDH-8-tumor-bearing rats progressively decreased as the KDH-8 tumor grew. IL-2 production from concanavalin-A-stimulated normal rat splenocytes was signficiantly inhibited by in vitro cultured KDH-8-tumor-cell-conditioned medium; this inhibition could be blocked by neutralizing the conditioned medium with anti-TGFß antibody. TGFß activities were found in KDH-8-tumor-tissue-conditioned medium without acid treatment and were found in tumor-cell-conditioned medium after acid treatment; TGFß mRNA and TGFß protein were found in cultured KDH-8 tumor cells. These results suggested that the KDH-8-tumor-derived TGFß might be involved in the inhibition of IL-2 production from splenocytes. To determine whether bleomycin chemotherapy could reduce tumor-derived TGFß and restore the immune responses, we treated KDH-8 tumor-bearing rats with bleomycin (5 mg/kg, one shot) at an appropriate time (before the occurrence of immunosuppression) resulting in a significiant reduction of TGFß activity in KDH-8 tumor tissues and restoration of IL-2 production from splenocytes of tumor-bearing rats; KDH-8 tumor growth ultimately regressed. In vitro experiments also showed that TGFß activity, mRNA expression, and protein synthesis in KDH-8 tumor cells were reduced by bleomycin treatment, and that bleomycin-treated-KDH-8-tumor-cell-conditioned medium did not inhibit IL-2 production from normal rat splenocytes. These results suggest that bleomycin treatment restored IL-2 production in tumor-bearing rats through reducing the tumor-derived TGFß.

Key Words: Immunosuppression, Transforming growth factor ß, Interleukin-2, Bleomycin, Tumor-bearing rats

Footnotes

This work was supported in part by grants for cancer research from the Japanese Ministry of Education, Science and Culture and from the Japanese Ministry of Health and Welfare

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