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Molecular and Cellular Biology, October 1998, p. 5678-5689, Vol. 18, No. 10
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Tumor Necrosis Factor Alpha Transcription in
Macrophages Is Attenuated by an Autocrine Factor That
Preferentially Induces NF-
B p50
Mark
Baer,1
Allan
Dillner,1
Richard C.
Schwartz,2
Constance
Sedon,1
Sergei
Nedospasov,3,4 and
Peter F.
Johnson1,*
Advanced BioScience Laboratories-Basic
Research Program1 and
Intramural
Research Support Program, SAIC Frederick, and Laboratory of
Molecular Immunoregulation, Division of Basic
Sciences,3 National Cancer
Institute-Frederick Cancer Research and Development Center,
Frederick, Maryland 21702-1201;
Department of Microbiology,
Michigan State University, East Lansing, Michigan
48824-11012; and
Engelhardt Institute of
Molecular Biology, Russian Academy of Sciences and Belozersky
Institute of Physico-Chemical Biology, Moscow State University,
Moscow 119899, Russia4
Received 4 December 1997/Returned for modification 3 February
1998/Accepted 14 July 1998
Macrophages are a major source of proinflammatory cytokines such as
tumor necrosis factor alpha (TNF-
), which are expressed during
conditions of inflammation, infection, or injury. We identified an
activity secreted by a macrophage tumor cell line that negatively regulates bacterial lipopolysaccharide (LPS)-induced expression of
TNF-
. This activity, termed TNF-
-inhibiting factor (TIF), suppressed the induction of TNF-
expression in macrophages, whereas induction of three other proinflammatory cytokines (interleukin-1
[IL-1
], IL-6, and monocyte chemoattractant protein 1) was
accelerated or enhanced. A similar or identical inhibitory activity was
secreted by IC-21 macrophages following LPS stimulation. Inhibition of TNF-
expression by macrophage conditioned medium was associated with
selective induction of the NF-
B p50 subunit. Hyperinduction of p50
occurred with delayed kinetics in LPS-stimulated macrophages but not in
fibroblasts. Overexpression of p50 blocked LPS-induced transcription
from a TNF-
promoter reporter construct, showing that this
transcription factor is an inhibitor of the TNF-
gene. Repression of
the TNF-
promoter by TIF required a distal region that includes
three NF-
B binding sites with preferential affinity for p50
homodimers. Thus, the selective repression of the TNF-
promoter by
TIF may be explained by the specific binding of inhibitory p50
homodimers. We propose that TIF serves as a negative autocrine signal
to attenuate TNF-
expression in activated macrophages. TIF is
distinct from the known TNF-
-inhibiting factors IL-4, IL-10, and
transforming growth factor
and may represent a novel cytokine.
*
Corresponding author. Mailing address: Advanced
BioScience Laboratories-Basic Research Program, National Cancer
Institute-Frederick Cancer Research and Development Center,
Frederick, MD 21702-1201. Phone: (301) 846-1627. Fax: (301)
846-5991. E-mail: johnsopf{at}ncifcrf.gov.
Molecular and Cellular Biology, October 1998, p. 5678-5689, Vol. 18, No. 10
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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