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Cell Cycle-specific Effects of Tumor Necrosis Factor¹

Sloan-Kettering Institute for Cancer Research, New York, New York 10021

The immediate effect of tumor necrosis factor (TNF) added to cultures of L-cells is cytostasis, manifested as cell arrest in G₂. This effect prevails during the initial 4 hr when the number of G₂ cells increases markedly in the absence of any significant cell death in the culture. Shortly thereafter, the cytolytic effect becomes apparent; extensive cell lysis can be detected after 7 hr of exposure to TNF. After 24 hr nearly all cells are lysed. Results of experiments in which the effects of TNF on the kinetics of cell progression through various phases of the cell cycle were studied indicate that in the presence of TNF cells do progress through G₂, although with considerable delay, and reach mitosis. Most cells die (undergo lysis) specifically at late stages of mitosis (telophase) or soon after cytokinesis. Sensitivity of cells to the lytic effect of TNF is increased by cell arrest in mitosis with Colcemid or vinblastine. TNF exerts little effect on rates of cell progression through G₁ or S phases of the cell cycle, although few cells die during S phase. Nonlysed cells from cultures treated with TNF do not show any changes in nuclear chromatin, suggesting that neither DNA nor nuclear proteins are the primary targets of the TNF. The present data implicate metabolic changes which occur during mitosis (cytokinesis), perhaps associated with synthesis or assembly of cell membrane components, as being responsible for increased cell sensitivity towards the cytolytic effect of TNF. The mechanism of the early cytostatic effect of the factor is unknown.

¹ Supported by Grants CA28704 and 23296 from the National Cancer Institute.

² To whom requests for reprints should be addressed, at Sloan-Kettering Institute for Cancer Research, Walker Laboratory, 145 Boston Post Road, Rye, N. Y. 10580.

Received 3/11/83. Accepted 9/28/83.

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