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Specific repression of granulocyte-macrophage and granulocyte colony-
stimulating factor gene expression in interleukin-1-stimulated endothelial
cells with antisense oligodeoxynucleotides
GM Segal, TD Smith, MC Heinrich, FS Ey and GC Bagby
Department of Medicine, Oregon Health Sciences University, Portland
97201-3098.
Antisense oligodeoxynucleotides (ODNs) have been used to effect the
specific inhibition of cellular gene expression. We have evaluated the
application of this approach to the inhibition of interleukin-1 (IL-1)-
induced granulocyte-macrophage colony-stimulating factor (GM-CSF) and
granulocyte colony-stimulating factor (G-CSF) expression in cultured human
umbilical vein endothelial cells. Antisense ODNs or control ODNs (sense
ODNs or missense ODNs containing random base substitutions) were added to
cultures of endothelial cells, the cells were induced with IL- 1 alpha, and
the conditioned media were assayed for GM-CSF and G-CSF by quantitative
bioassays and for immunoreactive GM-CSF by enzyme immunoassay. Antisense
ODNs complementary to the first 15 or 18 bases of the translation start
sites of GM-CSF or G-CSF mRNAs inhibited, in a concentration-dependent
fashion, the IL-1-stimulated expression of the corresponding factor, but
did not affect expression of the other factor. Control ODNs did not affect
GM-CSF or G-CSF expression. Exposure to a GM-CSF antisense ODN, but not a
control ODN, substantially reduced cytoplasmic GM-CSF mRNA levels in
IL-1-stimulated endothelial cells. Neither ODN affected levels of
endothelial leukocyte adhesion molecule (ELAM)1 or
glyceraldehyde-3-phosphate dehydrogenase mRNAs. We conclude that antisense
ODNs complementary to the translation start sites of GM-CSF or G-CSF mRNAs
inhibit expression of the corresponding factor in a sequence-specific
fashion and this effect is mediated, at least in part, by reduction in the
cytoplasmic level of the targeted mRNA. Moreover, IL-1-induced GM-CSF or
G-CSF expression does not depend on expression of the other factor.
Volume 80,
Issue 3,
pp. 609-616,
08/01/1992
Copyright © 1992 by The American Society of Hematology
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