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Interleukin-1, tumor necrosis factor, and the production of colony-
stimulating factors by cultured mesenchymal cells
CA Sieff, CM Niemeyer, SJ Mentzer and DV Faller
Division of Hematology and Pediatric Oncology, Children's Hospital, Boston,
MA 02115.
Although the genes for four hematopoietic colony-stimulating factors (CSFs)
have been cloned, neither the mechanism of the regulation of their
production nor their cellular origins have been established with certainty.
Monocytes are known to produce colony-stimulating and burst- promoting
activities, as well as several monokines such as interleukin- 1 (IL-1) and
tumor necrosis factor (TNF). These monokines indirectly stimulate other
mesenchymal cells to produce certain colony-stimulating factors such as
granulocyte-macrophage CSF (GM-CSF). To determine whether monocytes produce
other CSFs and if so, to compare the mechanism of regulation of production
with that of endothelial cells and fibroblasts, we investigated the
synthesis of CSFs by monocytes, human umbilical vein endothelial cells, and
fibroblasts. We used total cellular RNA blot analysis to determine
interleukin-3 (IL-3), GM-CSF, granulocyte CSF (G-CSF), and monocyte CSF
(M-CSF) messenger RNA (mRNA) content and immunoprecipitation or bioassay to
confirm the presence of the specific secreted proteins. The results
indicate that M-CSF mRNA and protein are produced constitutively by all
three cell types and their level of expression does not increase after
induction. In contrast, GM-CSF and G-CSF mRNAs are barely detectable in
uninduced monocytes and show an increase in expression after
lipopolysaccharide treatment. Retrovirus-immortalized endothelial cells,
unlike primary endothelial cells or both primary and immortalized
fibroblasts, produce IL-1 constitutively; this correlates with their
constitutive production of GM-CSF and G-CSF. IL-3 mRNA was not detectable
in any of these cells either before or after induction. The results
indicate that these mesenchymal cells can produce three CSFs: GM-CSF,
G-CSF, and M-CSF; furthermore, the data suggest that the mechanism of
regulation of M-CSF production is different from that of GM-CSF and G-CSF,
and that the latter two inducible CSFs are regulated by different factors
in monocytes compared with the other mesenchymal cells.
Volume 72,
Issue 4,
pp. 1316-1323,
10/01/1988
Copyright © 1988 by The American Society of Hematology
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