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Macrophage tumor necrosis factor-alpha release is induced by contact with some tumors
J D Hasday1, E M Shah, A P Lieberman
1Department of Medicine, University of Maryland School of Medicine, Baltimore 21201.
Abstract:
The purpose of this study was to determine whether macrophages were directly stimulated by tumor cells to release TNF-alpha. We found that several murine and human tumor cell lines and crude cell membrane vesicles prepared from these tumor cells stimulated pyran copolymer-elicited murine peritoneal macrophages (PEM) to release as much as 362 +/- 69 (mean +/- SE) units of TNF activity per 10(6) PEM in vitro. By contrast, several nontransformed cells, including Con A-stimulated splenic leukocytes and CTLL cloned T lymphocytes, failed to stimulate PEM to release TNF. Antibody and complement-mediated depletion of macrophages abrogated the release of TNF; whereas depletion of NK cells and T lymphocytes did not affect tumor-stimulated TNF release, suggesting that tumor cells directly stimulated PEM to release TNF. Tumor-stimulated TNF release was rapid, peaking in 2 to 3 h with subsequent loss of TNF activity from the medium. In the absence of tumor, PEM contained detectable levels of TNF mRNA, but did not release functionally active TNF. The addition of P815 tumor cell membrane vesicles increased both TNF mRNA levels, peaking at 1 to 2 h, and release of high levels of TNF activity. Confounding effects of endotoxin were excluded by the resistance of tumor-stimulated TNF release to neutralization by polymixin B, and by the equivalent responsiveness of PEM from endotoxin-resistant (C3H/HeJ) and endotoxin-sensitive (C3H/HeN) mice to stimulation by tumor cells. Factors which stimulated PEM to release TNF could be extracted from tumor cell membrane, with 77% of the macrophage-stimulating activity recoverable in aqueous phase. In conclusion, we have demonstrated that some tumor cell lines express specific characteristics which can be recognized by macrophages and which stimulate macrophages to release TNF.
Insights
Tumor cells directly stimulate macrophages to release tumor necrosis factor-alpha (TNF). This study confirms tumor cells possess specific characteristics recognized by macrophages, triggering TNF release essential for immune response.
Area of Science:
- Immunology
- Cancer Biology
Background:
- Macrophages are key immune cells involved in tumor surveillance.
- Tumor necrosis factor-alpha (TNF) plays a crucial role in inflammation and immunity.
- The direct interaction between tumor cells and macrophages in TNF release is not fully understood.
Purpose of the Study:
- To investigate whether tumor cells directly stimulate macrophages to release TNF-alpha.
- To identify the characteristics of tumor cells that trigger TNF release from macrophages.
Main Methods:
- Utilized murine and human tumor cell lines and their membrane vesicles to stimulate macrophages in vitro.
- Employed antibody and complement-mediated depletion to identify involved immune cells (macrophages, NK cells, T lymphocytes).
- Assessed TNF mRNA levels and activity in macrophages post-stimulation, excluding endotoxin effects.
Main Results:
- Tumor cell lines and membrane vesicles significantly stimulated macrophages to release TNF-alpha.
- Non-transformed cells did not induce TNF release, while macrophage depletion abrogated it.
- TNF release was rapid, peaking within 2-3 hours, and was independent of endotoxin contamination.
Conclusions:
- Demonstrated that specific tumor cell characteristics directly stimulate macrophages to release TNF.
- Macrophage activation by tumor cells involves recognition of specific tumor cell surface molecules.
- Findings highlight a direct pathway for tumor-induced immune activation via TNF release.