Transforming growth factor beta 1 (TGF-beta 1) produced in tumour tissue after chemotherapy acts as a lymphokine-activated killer attractant

Abstract

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.