Tumor necrosis factor-alpha mediates both apoptotic cell death and cell proliferation in a human hematopoietic cell line dependent on mitotic activity and receptor subtype expression

The TF-1 human erythroleukemic cell line exhibits opposing physiological re sponses toward tumor necrosis factor-alpha (TNF) treatment, dependent upon the mitotic state of the cells. Mitotically active cells in log growth resp ond to TNF by rapidly undergoing apoptosis whereas TNF exposure stimulates cellular proliferation in mitotically quiescent cells, The concentration-de pendent TNF-induced apoptosis was monitored by cellular metabolic activity and confirmed by both DNA epifluorescence and DNA fragmentation. Moreover, these responses could be detected by measuring extracellular acidification activity, enabling rapid prediction (within similar to 1.5 h of TNF treatme nt) of the fate of the cell in response to TNF. Growth factor resupplementa tion of quiescent cells, resulting in reactivation of cell cycling, altered TNF action from a proliferative stimulus to an apoptotic signal. Expressio n levels of the type II TNF receptor subtype (p75TNFR) were found to correl ate with sensitivity to TNF-induced apoptosis. Pretreatment of log growth T F-1 cells with a neutralizing anti-p75TNFR monoclonal antibody inhibited TN F-induced apoptosis by greater than 80%. Studies utilizing TNF receptor sub type-specific TNF mutants and neutralizing antisera implicated p75TNFR in T NF-dependent apoptotic signaling. These data show a bifunctional physiologi cal role for TNF in TF-1 cells that is dependent on mitotic activity and co ntrolled by the p75TNFR.