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Ability of flt3 ligand to stimulate the in vitro growth of primitive murine
hematopoietic progenitors is potently and directly inhibited by
transforming growth factor-beta and tumor necrosis factor-alpha
SE Jacobsen, OP Veiby, J Myklebust, C Okkenhaug and SD Lyman
Hipple Cancer Research Center, Dayton, OH 45439-2092, USA.
The recently cloned flt3 ligand (FL) stimulates the growth of primitive
hematopoietic progenitor cells through synergistic interactions with
multiple other cytokines. The present study is the first demonstrating
cytokines capable of inhibiting FL-stimulated hematopoietic cell growth.
Tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta
1 (TGF-beta l) potently inhibited the clonal growth of murine Lin-Sca-l+
bone marrow progenitors stimulated by FL alone or in combination with
granulocyte colony-stimulating factor (G-CSF), stem cell factor (SCF),
interleukin (IL)-3, IL-6, IL-11, or IL-12. TGF-beta 1 inhibited more than
96% of the myeloid colony formation in response to these cytokine
combinations, whereas TNF-alpha reduced the number of colonies by 58% to
96% depending on the cytokine by which FL was combined. In addition, both
TNF-alpha and TGF-beta 1 inhibited more than 90% of B220+ cell production
from B220- bone marrow cells stimulated by FL + IL-7. The effects of
TNF-alpha and TGF-beta 1 appeared to be due to a direct effect and on the
early progenitors because the inhibition was observed at the single cell
level, and because delayed addition of the two inhibitors for only 48 hours
dramatically reduced their inhibitory effects. A neutralizing anti-TGF-
beta antibody showed the presence of endogenous TGF-beta in the cultures
and potently enhanced the ability of FL to stimulate progenitor cell growth
in the absence of other cytokines. Agonistic antibodies specifically
activating the p75 TNF receptors were more efficient than wild type murine
TNF-alpha in signaling growth inhibition of Lin-Sca-l+ progenitor cells,
whereas the p55 agonist had less effect than murine TNF-alpha. Finally,
TGF-beta increased the number of FL + IL-11-stimulated Lin-Sca-1+ cells in
the G1 phase of the cell cycle with 76%, whereas TNF-alpha only had a
marginal effect on cell cycle distribution. Thus, TGF-beta, TNF-alpha, and
p75 TNF receptor agonists are potent direct inhibitors of FL-stimulated
progenitor cell growth in vitro.
Volume 87,
Issue 12,
pp. 5016-5026,
06/15/1996
Copyright © 1996 by The American Society of Hematology
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