Tumor necrosis factor and human hematopoiesis: II. Inhibition and mode of action on normal and chronic myelogenous leukemia-derived granulocyte-macrophage progenitor cells.
Recombinant technology-produced tumor necrosis factor alpha (rTNF-alpha) inhibits clonogenic growth of normal granulocyte-macrophage colony-forming cells (GM-CFC) when it is continuously present in the culture medium. In our studies, day 7 and day 14 GM-CFC were inhibited and showed similar response. A decrease in the number of large colonies accounted for most of the inhibition, whereas growth of small clusters was inhibited to a lesser extent. Comparable inhibition was observed when bone marrow cells were cloned at low (2.5 x 10(4)/ml) or high (10 x 10(4)/ml) cell densities. A similar degree of inhibition by rTNF-alpha was found when conditioned medium from the human placenta or a bladder carcinoma cell line was used as the source of the colony-stimulating factors (CSF). The dose-response curve of GM-CFC to rTNF-alpha was sigmoidal, the maximum inhibition (90%) occurring at approximately 100 ng/ml of rTNF-alpha. Short-term treatment of bone marrow in suspension culture for 2 hr did not affect the subsequent colony formation, suggesting that TNF had an antiproliferative rather than a direct toxic effect on normal GM-CFC. GM-CFC derived from previously untreated patients with Philadelphia chromosome-positive chronic myelogenous leukemia (CML) showed an in vitro dose response to rTNF-alpha similar to that of normal GM-CFC. Inhibition of colony formation by CML-derived GM-CFC was more pronounced than GM-CFC from normal marrows, especially at low concentrations of rTNF-alpha. An increase in the concentration of rTNF-alpha above 250 ng/ml had no further effect on colony formation.(ABSTRACT TRUNCATED AT 250 WORDS)
D001854:Bone Marrow Cells; D002999:Clone Cells; D004305:Dose-Response Relationship, Drug; D006098:Granulocytes / Q000187:drug effects; D006410:Hematopoiesis / Q000187:drug effects*; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology*; D008264:Macrophages / Q000187:drug effects; D011994:Recombinant Proteins / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma