Tumor Necrosis Factor Alpha Transcription in Macrophages Is Attenuated by an Autocrine Factor That Preferentially Induces NF-kappa B p50

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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 expressedduring conditions of inflammation, infection, or injury. We identifiedan activity secreted by a macrophage tumor cell line that negativelyregulates bacterial lipopolysaccharide (LPS)-induced expressionof TNF- $alpha$ . This activity, termed TNF- $alpha$ -inhibiting factor (TIF),suppressed the induction of TNF- $alpha$ expression in macrophages, whereasinduction of three other proinflammatory cytokines (interleukin-1 $beta$ [IL-1 $beta$ ], IL-6, and monocyte chemoattractant protein 1) was acceleratedor enhanced. A similar or identical inhibitory activity was secretedby IC-21 macrophages following LPS stimulation. Inhibition ofTNF- $alpha$ expression by macrophage conditioned medium was associatedwith selective induction of the NF- $kappa$ B p50 subunit. Hyperinductionof p50 occurred with delayed kinetics in LPS-stimulated macrophagesbut not in fibroblasts. Overexpression of p50 blocked LPS-inducedtranscription from a TNF- $alpha$ promoter reporter construct, showingthat this transcription factor is an inhibitor of the TNF- $alpha$ gene.Repression of the TNF- $alpha$ promoter by TIF required a distal regionthat includes three NF- $kappa$ B binding sites with preferential affinityfor p50 homodimers. Thus, the selective repression of the TNF- $alpha$ promoter by TIF may be explained by the specific binding of inhibitoryp50 homodimers. We propose that TIF serves as a negative autocrinesignal 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 novelcytokine.

^* Corresponding author. Mailing address: Advanced BioScience Laboratories-Basic Research Program, National Cancer Institute-FrederickCancer 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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Tumor Necrosis Factor Alpha Transcription in Macrophages Is Attenuated by an Autocrine Factor That Preferentially Induces NF-B p50

Tumor Necrosis Factor Alpha Transcription in Macrophages Is Attenuated by an Autocrine Factor That Preferentially Induces NF- $kappa$ B p50