Restoration of interleukin-2 production in tumor-bearing rats through reducing tumor-derived transforming growth factor beta by treatment with bleomycin.
We studied mechanisms of immunosuppression caused by tumor-derived transforming growth factor-beta (TGF beta) 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 significantly inhibited by in vitro cultured KDH-8-tumor-cell-conditioned medium; this inhibition could be blocked by neutralizing the conditioned medium with anti-TGF beta antibody. TGF beta activities were found in KDH-8-tumor-tissue-conditioned medium without acid treatment and were found in tumor-cell-conditioned medium after acid treatment; TGF beta mRNA and TGF beta protein were found in cultured KDH-8 tumor cells. These results suggested that the KDH-8-tumor-derived TGF beta might be involved in the inhibition of IL-2 production from splenocytes. To determine whether bleomycin chemotherapy could reduce tumor-derived TGF beta 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 significant reduction of TGF beta 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 TGF beta 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 TGF beta.
Yuan
L
L
Laboratory of Pathology, Hokkaido University School of Medicine, Sapporo, Japan.
Kuramitsu
Y
Y
Li
Y
Y
Kobayashi
M
M
Hosokawa
M
M
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology* / Q000627:therapeutic use; D001483:Base Sequence; D001761:Bleomycin / Q000494:pharmacology* / Q000627:therapeutic use; D002455:Cell Division / Q000187:drug effects; D017077:Culture Media, Conditioned; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D007108:Immune Tolerance / Q000187:drug effects*; D007376:Interleukin-2 / Q000096:biosynthesis* / Q000235:genetics; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy / Q000276:immunology*; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D009368:Neoplasm Transplantation; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000494:pharmacology; D013154:Spleen / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000494:pharmacology / Q000502:physiology
D000903:Antibiotics, Antineoplastic; D017077:Culture Media, Conditioned; D007376:Interleukin-2; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D001761:Bleomycin