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Gene Expression in Macrophages: Regulation by NF-
B Is Independent of c-Jun or C/EBPß1
*
Department of Medicine, Division of Arthritis, Veterans Administration Lakeside Medical Center, and Northwestern University Medical School, Chicago, IL 60611;
Biomarkers and Prevention Research Branch, National Cancer Institute, National Institutes of Health, Rockville, MD 20805;
Signal Pharmaceuticals, Inc., San Diego, CA 92121; and
§
Immunobiology Research Center, Beth Israel Deaconess Medical Center, Boston, MA 02215
The interaction of transcription factors is critical in the
regulation of gene expression. This study characterized the mechanism
by which NF-
B family members interact to regulate the human TNF-
gene. A 120-bp TNF- promoter-reporter, possessing binding sites for
NF-B (B3), C/EBPß (CCAAT/enhancer binding protein ß), and
c-Jun, was activated by cotransfection of plasmids expressing the
wild-type version of each of these transcription factors. Employing
adenoviral vectors, dominant-negative versions of NF-B p65, and
c-Jun, but not C/EBPß, suppressed (p <
0.05–0.001) LPS-induced TNF- secretion in primary human
macrophages. Following LPS stimulation, NF-B p50/p65 heterodimers
bound to the B3 site and c-Jun to the -103 AP-1 site of the TNF-
promoter. By transient transfection, NF-B p65 and p50
synergistically activated the TNF- promoter. In contrast, no synergy
was observed between NF-B p65, with or without NF-B p50, and
c-Jun or C/EBPß, even in the presence of the coactivator p300. The
contribution of the upstream B binding sites was also examined.
Following LPS stimulation, the B1 site bound both NF-B p50/p65
heterodimers and p50 homodimers. The binding by NF-B p50 homodimers
to the B1, but not to the B3, site contributed to the inability
of macrophages to respond to a second LPS challenge. In summary,
adjacent B3 and AP-1 sites in the human TNF- promoter contribute
independently to LPS-induced activation. Although both the B1 and
B3 sites bound transcriptionally active NF-B p50/p65
heterodimers, only the B1 site contributed to down-regulation by
NF-B p50 homodimers.
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