© 1995 American Heart Association, Inc.
Articles |
Transcriptional Activation of the Macrophage-Colony Stimulating Factor Gene by Minimally Modified LDL
Involvement of Nuclear Factor-
B
From the Divisions of Endocrinology and Medical Genetics, Department of Medicine (T.B.R., N.K.M.), Harbor-UCLA Medical Center, Torrance, Calif, and the Jikei University School of Medicine, Department of Medicine (H.Y.), Aoto Hospital, Katsushika-ku, Tokyo, Japan.
Correspondence to Dr Tripathi B. Rajavashisth, Division of Endocrinology, RB-1, Harbor-UCLA Medical Center, 1124 W Carson St, Torrance, CA 90502-2064.
Abstract Minimally modified LDL (MM-LDL), obtained by mild
iron oxidation or prolonged storage at 4°C, has been shown to induce
the expression of macrophage-colony stimulating factor
(M-CSF) in cultured aortic endothelial cells. To
examine whether other cell types also respond to MM-LDL, we
investigated its effect on the expression of M-CSF mRNA in mouse
L-cells and human aortic smooth muscle cells. Both L-cells and human
aortic smooth muscle cells showed increased levels of M-CSF mRNA in
response to 10 to 200 µg/mL MM-LDL in a dose-dependent manner.
This allowed us to use mouse L-cells as a model to study the mechanism
involved in MM-LDL–mediated increase in M-CSF mRNA. Nuclear run-on
assays showed that M-CSF gene transcription was activated by
MM-LDL. In the present study, we identified specific elements that
conferred MM-LDL–mediated transcriptional activation of the human
M-CSF gene. Chimeric constructs containing sequential deletions in the
5'-promoter region of the M-CSF gene linked to a reporter
chloramphenicol acetyltransferase (CAT) gene were transfected into
mouse L-cells. The human M-CSF promoter region extending upstream from
the transcription start site to nucleotide -406 showed
maximum induction of CAT activity by MM-LDL. Induction of CAT activity
was drastically reduced, with a deletion plasmid lacking the promoter
region -406 to -344. A functional nuclear factor (NF)–
B binding
site present in this critical region was required for
MM-LDL–mediated induction of CAT activity since an internal deletion
construct lacking this element showed significant loss of
transcriptional activation. Similar results also were obtained with the
use of bovine aortic endothelial cells, suggesting that
part of the mechanism is shared in different cell types. Gel shift
assays with bovine aortic endothelial cell nuclear
extracts revealed that this element binds to MM-LDL–inducible nuclear
protein(s) that exhibited DNA binding specificity of NF-B and
cross-reacted to NF-B–specific antibodies. Taken together,
these results are consistent with the involvement of NF-B in
the transcriptional activation of the human M-CSF gene by MM-LDL.
Key Words: transcriptional activation • macrophage-colony stimulating factor • lipoproteins • nuclear factor-B • atherogenesis
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