Transforming growth factor-beta trans-modulates the expression of colony stimulating factor receptors on murine hematopoietic progenitor cell lines.
Transforming growth factor beta (TGF-beta) is a potent and selective growth inhibitor of early hematopoietic progenitors and leukemic cells. The cellular mechanism(s) underlying this antiproliferative effect is, however, currently unknown. In the present study, we demonstrate that TGF-beta inhibits the expression of granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin 3 (IL-3), and granulocyte-CSF (G-CSF) receptors on murine factor-dependent and independent hematopoietic progenitor cell lines without a significant change in receptor affinity. A maximum reduction in GM-CSF receptor numbers of 65% to 77% was observed by 96-hour incubation with TGF-beta. The TGF-beta induced trans-down-modulation of GM-CSF receptors was prolonged, noncytotoxic but reversible, and not due to endogenous production of GM-CSF. The TGF-beta induced reduction in CSF receptor numbers preceded TGF-beta's growth inhibitory action. In addition, the ED50 (1 to 10 pmol/L) for TGF-beta's CSF receptor modulatory and antiproliferative effect was similar. The effect of TGF-beta on cell surface CSF receptor expression was specific, because the expression of other cell surface proteins (Ly 5 and Ly 17) was not affected by TGF-beta treatment, and because other growth inhibitors (tumor necrosis factor and interferon) did not affect CSF receptor expression. These data suggest that the downregulation of the growth of hematopoietic progenitor cells by TGF-beta involves reducing the cell surface expression on growth factor receptors.
Jacobsen
S E
SE
Laboratory of Molecular Immunoregulation, NCI, Frederick Cancer Research and Development Center, MD 21702.
Ruscetti
F W
FW
Dubois
C M
CM
Lee
J
J
Boone
T C
TC
Keller
J R
JR
D000818:Animals; D001853:Bone Marrow / Q000502:physiology; D001854:Bone Marrow Cells; D002460:Cell Line; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D007377:Interleukin-3 / Q000378:metabolism; D007700:Kinetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000187:drug effects / Q000378:metabolism*; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000187:drug effects / Q000378:metabolism*; D016185:Receptors, Interleukin-3 / Q000187:drug effects / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D007377:Interleukin-3; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D016185:Receptors, Interleukin-3; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D016179:Granulocyte Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor