Effects of recombinant tumor necrosis factor, lymphotoxin, and immune interferon on proliferation and differentiation of enriched hematopoietic precursor cells.

We compared the effects of recombinant (r) tumor necrosis factor (TNF) and lymphotoxin (rLT) on in vitro colony formation by erythroid, multipotential and granulocyte, monocyte (CFU-GM) precursor cells. Recombinant granulocyte, macrophage-colony stimulating factor and bone marrow preparations enriched for hematopoietic precursors were used in order to examine the direct effects of the cytokines on precursors in the absence of other soluble factors or mature cells that may influence colony formation. Both rTNF and rLT inhibited colony formation by erythroid and multipotential precursor cells. rTNF and rLT did not inhibit the more mature (day-7) CFU-GM, although a synergistic inhibition was observed when the cytokines were added to cultures together with recombinant interferon gamma (rIFN gamma). However, rTNF did inhibit day-7 CFU-GM when conditioned medium from the human bladder carcinoma cell line 5637 was used as a source of colony-stimulating activity. rTNF inhibited the more immature (day-14) CFU-GM regardless of the source of colony-stimulating activity used, and was a stronger inhibitor of day-14 CFU-GM than rLT, suggesting a difference in the biological effects of the two cytokines. Noninhibitory concentrations of rTNF or rIFN increased the number of monocyte colonies formed, identified by cytochemical staining. These data suggest a mechanism for TNF and IFN gamma-induced inhibition of CFU-GM through induction of monocyte differentiation rather than through a direct toxic effect.