A regulatory role for tumor necrosis factor (TNF) in ML-1 human myeloblastic leukemia cell maturation

ML-1 human myeloblastic leukemia cells are induced to differentiate to monocytes by conditioned medium (CM) derived from tetradecanoylphorbol acetate (TPA)-treated ML-1 cells. Antibodies to tumor necrosis factor (TNF) inhibited the differentiation-stimulating activity of CM, indicating that this activity is due to the presence of TNF in CM. TNF added to non-conditioned medium was as effective as CM in stimulating ML-1 cell differentiation. In the presence of a low (0.12 ng/ml) concentration of TPA, TNF-induced maturation was synergistically increased and Type I macrophages were formed. With higher (1-10 ng/ml) TPA concentrations, Type II macrophages were also obtained. As the TNF/TPA concentration increased, ML-1 cell differentiation was increasingly inhibited. Mature cells derived from ML-1 cells were found to secrete TNF at concentrations ranging from less than 2 U/ml to greater than 180 U/ml, the amount depending upon the number of cells and the stage of cell maturation. These results indicate that TNF participates in the regulation of precursor cell maturation. Low concentrations of TNF produced by small numbers of mature cells stimulate differentiation, whereas high concentrations of TNF generated by elevated numbers of macrophages inhibit the maturation process, possibly in combination with other cytokines. Because TNF serves as a competence factor for ML-1 cells, (Guan X.-P., Takuma T., Hromchak R. & Bloch A. (1990) Competence and progression in cell differentiation. Proc. Am. Assoc. Cancer Res. 31, 28.), the TNF-induced stimulation of differentiation depends additionally on the action of serum-contained differentiation-specific progression factors.