Transforming growth factor beta 1 (TGF-beta 1) produced in tumour tissue after chemotherapy acts as a lymphokine-activated killer attractant.
Using an under agarose migration (UAM) assay, we studied lymphokine-activated killer (LAK)-attractant activity in cultured conditioned medium of tumour tissues after chemotherapy as a possible mechanism of enhanced LAK cell accumulation into tumour tissues after chemotherapy. BMT-11 is a fibrosarcoma developed in C57BL/6 mice. The conditioned medium of BMT-11 tumour tissues obtained from mice treated with various anti-cancer drugs had chemotactic activity for LAK cells (LAK-attractant activity). mRNA expression of interleukin (IL)-1 alpha, IL-6, IL-8, interferon (IFN)-gamma, and tumour necrosis factor (TNF)-alpha was observed in untreated tumour tissues, which were not enhanced by cyclophosphamide treatment. mRNA expression of TGF-beta 1 was not detected in untreated tumour tissues by reverse transcription-polymerase chain reaction (RT-PCR), but was detected in tumour tissues treated with cyclophosphamide. Recombinant human TGF-beta 1 showed LAK-attractant activity at a concentration of 0.1 ng ml-1 and 1 ng ml-1, whereas fresh splenocytes were not attracted by TGF-beta 1. Anti-TGF-beta 1 antibody inhibited LAK-attractant activity in the conditioned medium of tumour tissues treated with cyclophosphamide to approximately 35% that of control at 100 micrograms ml-1. These findings indicate that TGF-beta 1 produced in the tumour tissues of mice treated with anti-cancer drugs could be a LAK attractant. By a 4 h 51Cr release assay of natural killer cell-resistant BMT-11 tumour cells, we observed that TGF-beta 1 at a concentration from 0.01 ng ml-1 to 10 ng ml-1 did not inhibit LAK activity in an effector phase. Taken together, we suggest that TGF-beta 1 produced in tumour tissues after chemotherapy participates in gathering transferred LAK cells and contributes to the therapeutic effects of transferred LAK cells.
Kuramitsu
Y
Y
Laboratory of Pathology, Hokkaido University School of Medicine, Sapporo, Japan.
Nishibe
M
M
Kobayashi
M
M
Togashi
Y
Y
Yuan
L
L
Takizawa
M
M
Okada
F
F
Hosokawa
M
M
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001483:Base Sequence; D002630:Chemotactic Factors / Q000096:biosynthesis / Q000494:pharmacology / Q000502:physiology*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000502:physiology*; D003520:Cyclophosphamide / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D005354:Fibrosarcoma / Q000188:drug therapy* / Q000378:metabolism*; D015979:Killer Cells, Lymphokine-Activated / Q000166:cytology* / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000494:pharmacology / Q000502:physiology*
D000970:Antineoplastic Agents; D002630:Chemotactic Factors; D016207:Cytokines; D012333:RNA, Messenger; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D003520:Cyclophosphamide