PMID- 8652814
OWN - NLM
STAT- MEDLINE
DCOM- 19960731
LR  - 20210216
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 87
IP  - 12
DP  - 1996 Jun 15
TI  - 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.
PG  - 5016-26
AB  - 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.
FAU - Jacobsen, S E
AU  - Jacobsen SE
AD  - Hipple Cancer Research Center, Dayton, OH 45439-2092, USA.
FAU - Veiby, O P
AU  - Veiby OP
FAU - Myklebust, J
AU  - Myklebust J
FAU - Okkenhaug, C
AU  - Okkenhaug C
FAU - Lyman, S D
AU  - Lyman SD
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Interleukin-11)
RN  - 0 (Interleukin-6)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Receptors, Tumor Necrosis Factor)
RN  - 0 (Recombinant Proteins)
RN  - 0 (Transforming Growth Factor beta)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 143011-72-7 (Granulocyte Colony-Stimulating Factor)
RN  - EC 2.7.10.1 (Flt3 protein, mouse)
RN  - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases)
RN  - EC 2.7.10.1 (fms-Like Tyrosine Kinase 3)
SB  - IM
MH  - Animals
MH  - Bone Marrow Cells
MH  - Cell Cycle/drug effects
MH  - Cell Division/drug effects
MH  - Cells, Cultured
MH  - Dose-Response Relationship, Drug
MH  - Granulocyte Colony-Stimulating Factor/pharmacology
MH  - Hematopoietic Stem Cells/*drug effects
MH  - Interleukin-11/pharmacology
MH  - Interleukin-6/pharmacology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Proto-Oncogene Proteins/*antagonists & inhibitors/pharmacology
MH  - Receptor Protein-Tyrosine Kinases/*antagonists & inhibitors/pharmacology
MH  - Receptors, Tumor Necrosis Factor/drug effects/physiology
MH  - Recombinant Proteins/pharmacology
MH  - Signal Transduction/drug effects
MH  - Transforming Growth Factor beta/*pharmacology
MH  - Tumor Necrosis Factor-alpha/*pharmacology
MH  - fms-Like Tyrosine Kinase 3
EDAT- 1996/06/15 00:00
MHDA- 1996/06/15 00:01
CRDT- 1996/06/15 00:00
PHST- 1996/06/15 00:00 [pubmed]
PHST- 1996/06/15 00:01 [medline]
PHST- 1996/06/15 00:00 [entrez]
AID - S0006-4971(20)61200-9 [pii]
PST - ppublish
SO  - Blood. 1996 Jun 15;87(12):5016-26.