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Transforming growth factor-beta inhibits interferon-gamma secretion by lymphokine-activated killer cells stimulated
H Naganuma1, A Sasaki, E Satoh
1Department of Neurosurgery, Yamanashi Medical University.
Abstract:
The effect of transforming growth factor-beta (TGF-beta) secreted by glioblastoma (T98G) cells on the secretion of interferon-gamma (IFN-gamma) by lymphokine-activated killer (LAK) cells stimulated with tumor cells was investigated in cocultures of LAK and Daudi cells supplemented with T98G culture supernatant, T98G culture supernatant preincubated with anti-TGF-beta 1 and anti-TGF-beta 2 neutralizing antibodies, anti-TGF-beta 1 and anti-TGF-beta 2 antibodies, or natural human TGF-beta 1 or recombinant human TGF-beta 2. LAK cells were incubated with anti-TGF-beta 1 and anti-TGF-beta 2 antibodies, and with T98G cells of which the supernatant contained both active and latent forms of TGF-beta 1 and TGF-beta 2, with or without neutralizing antibodies. Addition of the supernatant from T98G cells to LAK/Daudi culture caused inhibition of IFN-gamma secretion by LAK cells. The inhibition was abolished by pretreatment of the supernatants with anti-TGF-beta antibodies. Addition of TGF-beta 1 and TGF-beta 2 to the LAK/Daudi culture inhibited IFN-gamma secretion by LAK cells in a dose-dependent manner. Addition of anti-TGF-beta antibodies to the LAK culture resulted in increased IFN-gamma secretion. T98G cells failed to stimulate LAK cells to secrete more IFN-gamma. Addition of anti-TGF-beta antibodies to the LAK-T98G culture resulted in increased IFN-gamma secretion by LAK cells. These results suggest that most malignant glioma cells which secrete high levels of TGF-beta can inhibit IFN-gamma secretion by LAK cells even after tumor cell stimulation.
Insights
Transforming growth factor-beta (TGF-beta) from glioblastoma cells inhibits interferon-gamma (IFN-gamma) secretion by lymphokine-activated killer (LAK) cells. Neutralizing TGF-beta restored LAK cell function, indicating its immunosuppressive role in glioblastoma.
Area of Science:
- Immunology
- Cancer Biology
- Cell Signaling
Background:
- Glioblastoma (T98G) cells secrete transforming growth factor-beta (TGF-beta).
- Lymphokine-activated killer (LAK) cells are crucial for anti-tumor immunity.
- The interaction between TGF-beta and LAK cell function in glioblastoma is not fully understood.
Purpose of the Study:
- To investigate the effect of TGF-beta secreted by glioblastoma cells on IFN-gamma secretion by LAK cells.
- To determine if TGF-beta neutralization can restore LAK cell anti-tumor activity.
Main Methods:
- Co-culturing LAK cells with glioblastoma (T98G) cells or their supernatant.
- Utilizing neutralizing antibodies against TGF-beta 1 and TGF-beta 2.
- Measuring interferon-gamma (IFN-gamma) secretion by LAK cells via ELISA.
- Dose-response experiments with recombinant TGF-beta 1 and TGF-beta 2.
Main Results:
- T98G cell supernatant significantly inhibited IFN-gamma secretion by LAK cells.
- Pre-incubation of supernatant with anti-TGF-beta antibodies abolished this inhibition.
- Exogenous TGF-beta 1 and TGF-beta 2 inhibited IFN-gamma secretion in a dose-dependent manner.
- Addition of anti-TGF-beta antibodies to LAK-T98G co-cultures increased IFN-gamma secretion.
Conclusions:
- High levels of TGF-beta secreted by malignant glioma cells suppress IFN-gamma production by LAK cells.
- TGF-beta plays a significant immunosuppressive role in the glioblastoma tumor microenvironment.
- Targeting TGF-beta may be a potential strategy to enhance LAK cell-mediated anti-tumor immunity in glioblastoma.