Stimulation of granulopoiesis by transforming growth factor beta: synergy with granulocyte/macrophage-colony-stimulating factor.
Transforming growth factor beta 1 (TGF-beta 1) is known to inhibit the growth of immature hematopoietic progenitor cells, whereas more mature, lineage-restricted progenitors are not inhibited. In contrast, in the presence of saturating concentrations of granulocyte/macrophage-colony-stimulating factor (GM-CSF), TGF-beta promoted a 3- to 5-fold increase in the number and size (greater than 0.5 mm) of bone marrow colonies in a dose-dependent manner with an ED50 of 10-20 pM; TGF-beta 1 alone had no effect. Morphological examination showed an increase in granulocyte colonies. In suspension cultures, TGF-beta 1 and GM-CSF stimulated an increase in total viable cells with markedly enhanced neutrophilic differentiation and a concomitant decrease in the number of monocytes/macrophages by day 6 in culture. Limiting dilution analysis demonstrated a 2- to 5-fold increase in the frequency of progenitor cells that responded to GM-CSF plus TGF-beta 1 vs. GM-CSF alone. Bone marrow progenitors obtained from mice 3 days after treatment with 5-fluorouracil responded to a combination of GM-CSF and TGF-beta 1, whereas either factor alone had no effect. A single-cell assay identified a progenitor cell that directly responded to TGF-beta and GM-CSF. TGF-beta increased the number of GM-CSF receptors on bone marrow cells. Thus, TGF-beta 1 can act as a bifunctional mediator of hematopoietic cell growth, and TGF-beta 1 and GM-CSF act together to stimulate granulopoiesis as measured by large granulocyte colony formation; the progenitor cell is tentatively designated granulocyte burst-forming unit.
Keller
J R
JR
Biological Carcinogenesis and Development Program, Program Resources, Inc., Frederick, MD.
Jacobsen
S E
SE
Sill
K T
KT
Ellingsworth
L R
LR
Ruscetti
F W
FW
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects; D001854:Bone Marrow Cells; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003115:Colony-Stimulating Factors / Q000494:pharmacology; D004357:Drug Synergism; D005472:Fluorouracil / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D006098:Granulocytes / Q000166:cytology* / Q000187:drug effects; D006410:Hematopoiesis / Q000187:drug effects*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects; D007378:Interleukins / Q000494:pharmacology; D007700:Kinetics; D008264:Macrophages / Q000166:cytology / Q000187:drug effects; D051379:Mice; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D003115:Colony-Stimulating Factors; D007378:Interleukins; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D005472:Fluorouracil