Inhibition of Tumor Necrosis Factor-α and β Secretion by Lymphokine Activated Killer Cells by Transforming Growth Factor-β

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Abstract
Transforming growth factor-beta (TGF-beta) has a variety of immunosuppressive properties. We investigated the effect of TGF-beta secreted by glioblastoma (T98G) cells on the secretion of tumor necrosis factor-alpha and -beta (TNFs) by lymphokine activated killer (LAK) cells stimulated with tumor cells. The supernatant from T98G cells was preincubated with anti-TGF-beta 1 and -beta 2 neutralizing antibodies or untreated, 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 latent forms of TGF-beta 1 and TGF-beta 2, and the neutralizing antibodies were added to the coculture. TNFs activity in the supernatants from LAK/Daudi cultures was examined by a specific bioassay. Addition of the supernatant from T98G cells to LAK/Daudi culture resulted in the inhibition of TNFs secretion by LAK cells. The inhibition was abrogated by the pretreatment of the 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 antibodies to LAK culture resulted in an increase of TNFs secretion. These results 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-beta secreted and activated by glioblastoma cells suppresses the propagation of immune reaction by inhibiting TNFs secretion by activated lymphocytes adjacent to tumor cells.

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