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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-kappa 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-alpha ), 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-alpha . This activity, termed TNF-alpha -inhibiting factor (TIF), suppressed the induction of TNF-alpha expression in macrophages, whereas induction of three other proinflammatory cytokines (interleukin-1beta [IL-1beta ], 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-alpha expression by macrophage conditioned medium was associated with selective induction of the NF-kappa 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-alpha promoter reporter construct, showing that this transcription factor is an inhibitor of the TNF-alpha gene. Repression of the TNF-alpha promoter by TIF required a distal region that includes three NF-kappa B binding sites with preferential affinity for p50 homodimers. Thus, the selective repression of the TNF-alpha 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-alpha expression in activated macrophages. TIF is distinct from the known TNF-alpha -inhibiting factors IL-4, IL-10, and transforming growth factor beta  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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