INHIBITION OF TUMOR-NECROSIS FACTOR-ALPHA AND FACTOR-BETA SECRETION BY LYMPHOKINE-ACTIVATED KILLER-CELLS BY TRANSFORMING GROWTH-FACTOR-BETA

Transforming growth factor-beta (TGF-beta) has a variety of immunosupp ressive properties. We investigated the effect of TGF-beta secreted by glioblastoma (T98G) cells on the secretion of tumor necrosis factor-a lpha and -beta (TNFs) by lymphokine activated killer (LAK) cells stimu lated with tumor cells. The supernatant from T98G cells was preincubat ed with anti-TGF-beta 1 and -beta 2 neutralizing antibodies or untreat ed, and added to a coculture of LAK and Daudi cells. The neutralizing antibodies were added to LAK/Daudi and LAK culture, and natural human TGF-beta 1 and recombinant human TGF-beta 2 were also added to the LAK /Daudi culture. LAK cells were also cultured with T98G cells, of which the supernatant contained both active and latest forms of TGF-beta 1 and TGF-beta 2, and the neutralizing antibodies were added to the cocu lture. TNFs activity in the supernatants from LAK/Daudi cultures was e xamined by a specific bioassay. Addition of the supernatant from T98G cells to LAK/Daudi culture resulted in the inhibition of TNFs secretio n by LAK cells. The inhibition was abrogated by the pretreatment of th e supernatants with the anti-TGF-beta antibodies. Addition of TGF-beta 1 and TGF-beta 2 to LAK/Daudi culture inhibited TNFs secretion by LAK cells in a dose dependent manner. Addition of anti-TGF-beta antibodie s to LAK culture resulted in an increase of TNFs secretion. These resu lts suggest that, if tumor cells have the capacity to convert TGF-beta from a latent to an active form, the active TGF-beta suppresses TNFs secretion by LAK cells stimulated with the tumor cells, and that TGF-b eta secreted and activated by glioblastoma cells suppresses the propag ation of immune reaction by inhibiting TNFs secretion by activated lym phocytes adjacent to tumor cells.