Transforming growth factor beta 1 functions in monocytic differentiation of hematopoietic cells through autocrine and paracrine mechanisms.
This study examined the role of transforming growth factor beta 1 (TGF-beta 1) in monocytic differentiation of hematopoietic cells. TGF-beta 1 and retinoic acid (RA) inhibited HL-60 cell growth in a dose-dependent fashion. Treatment of HL-60 cells with a combination of TGF-beta 1 and a 50% optimal dose of RA (RA + TGF-beta 1) resulted in increased growth suppression compared to the individual treatments. Morphological studies revealed that TGF-beta 1 induced promonocytic differentiation (68%), RA induced granulocytic differentiation (98%), and RA + TGF-beta 1 induced monocytic (54%) and granulocytic (46%) differentiation of HL-60 cells. Induction of the monocyte-specific marker, nonspecific esterase, was markedly increased by TGF-beta 1 and RA + TGF-beta 1 treatment but not by RA treatment. Both TGF-beta 1 treatment and RA treatment increased TGF-beta ligand and TGF-beta receptor protein and mRNA levels. To determine whether RA mediated HL-60 cell growth inhibition and differentiation through the autocrine expression of TGF-beta 1, experiments using TGF-beta 1 antisense oligonucleotides or TGF-beta 1-neutralizing antibodies were conducted. TGF-beta 1 antisense oligonucleotides and neutralizing antibodies partially blocked RA-induced inhibition of proliferation, and TGF-beta 1 antisense oligonucleotides reversed RA-induced granulocytic maturation, demonstrating that RA signals autocrine expression of TGF-beta 1 and TGF-beta receptors. The effect of TGF-beta 1 on normal hematopoiesis was also studied using primary human fetal liver cells. TGF-beta 1 alone and in the presence of interleukin 3 promoted macrophage differentiation of primitive fetal liver cells. Cell surface expression of the monocyte/macrophage-specific marker c-fms was increased 3.1-fold following TGF-beta 1 treatment. In addition, TGF-beta 1-treated cells displayed a 51% increase in phagocytosis as compared to interleukin 3-treated control cells. These studies define a role for TGF-beta 1 in the autocrine and paracrine regulation of monocyte/macrophage differentiation.
Turley
J M
JM
Laboratory of Leukocyte Biology, National Cancer Institute, Frederick, Maryland 21702, USA.
Falk
L A
LA
Ruscetti
F W
FW
Kasper
J J
JJ
Francomano
T
T
Fu
T
T
Bang
O S
OS
Birchenall-Roberts
M C
MC
D015415:Biomarkers; D002454:Cell Differentiation; D002455:Cell Division; D002478:Cells, Cultured; D004950:Esterases / Q000032:analysis; D015870:Gene Expression; D006098:Granulocytes / Q000166:cytology; D018922:HL-60 Cells; D006410:Hematopoiesis / Q000502:physiology*; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology; D008099:Liver / Q000166:cytology / Q000196:embryology; D009000:Monocytes / Q000166:cytology*; D016376:Oligonucleotides, Antisense; D010587:Phagocytosis; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000032:analysis; D018125:Receptors, Transforming Growth Factor beta / Q000032:analysis / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014212:Tretinoin / Q000494:pharmacology*
D015415:Biomarkers; D007377:Interleukin-3; D016376:Oligonucleotides, Antisense; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D014212:Tretinoin; D016186:Receptor, Macrophage Colony-Stimulating Factor; D004950:Esterases