THE PROMOTING EFFECT OF TUMOR-NECROSIS-FACTOR-ALPHA IN RADIATION-INDUCED CELL-TRANSFORMATION

The ability of tumour necrosis factor alpha (TNF-alpha), a potent endo genous inflammatory agent, to promote malignant transformation of Syri an hamster embryo cells (SHE) initiated by a 0.5-Gy dose of alpha-part icles was investigated. Opsonized zymosan particles, which were phagoc ytosed by a human macrophage-like cell line, triggered TNF-alpha produ ction from U937 cells. This cell supernatant could significantly incre ase the transformation frequency (TF) of primary SHE cells previously irradiated by a 0.5-Gy dose of alpha-particles. The TF decreased signi ficantly if monoclonal antibody against TNF-alpha was added to the sup ernatant. Similarly, recombinant human TNF-alpha (rhTNF-alpha) increas ed the TF of alpha-irradiated primary SHE cells to an even greater ext ent. Addition of TNF-alpha to subcultures of irradiated SHE cells perm itted the continuous propagation of these primary cells. In contrast, both TNF-alpha-treated control and alpha-irradiated cells without subs equent TNF-alpha treatment senesced after 7-15 passages. Irradiated SH E cells treated continuously with TNF-alpha could be subcultured over 40 passages and produced fibrosarcomas upon inoculation into nude mice . Our results provide the first evidence that TNF-alpha released by ac tivated macrophages may contribute to the process of malignant transfo rmation initiated by low-dose alpha-particles.