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Molecular and Cellular Biology, December 2000, p. 9113-9119, Vol. 20, No. 24
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Functional Consequences of a Polymorphism Affecting NF-kappa B p50-p50 Binding to the TNF Promoter Region

Irina A. Udalova,1,* Anna Richardson,1 Agnes Denys,2 Clive Smith,2 Hans Ackerman,1 Brian Foxwell,2 and Dominic Kwiatkowski1

Molecular Infectious Disease Group, Institute of Molecular Medicine, Oxford University, Oxford,1 and Kennedy Institute of Rheumatology, Charing Cross Hospital, London,2 United Kingdom

Received 22 August 2000/Accepted 20 September 2000

Stimulation of the NF-kappa B pathway often causes p65-p50 and p50-p50 dimers to be simultaneously present in the cell nucleus. A natural polymorphism at nucleotide -863 in the human TNF promoter (encoding tumor necrosis factor [TNF]) region provides an opportunity to dissect the functional interaction of p65-p50 and p50-p50 at a single NF-kappa B binding site. We found that this site normally binds both p65-p50 and p50-p50, but a single base change specifically inhibits p50-p50 binding. Reporter gene analysis in COS-7 cells expressing both p65-p50 and p50-p50 shows that the ability to bind p50-p50 reduces the enhancer effect of this NF-kappa B site. Using an adenoviral reporter assay, we found that the variant which binds p50-p50 results in a reduction of lipopolysaccharide-inducible gene expression in primary human monocytes. This finding adds to a growing body of experimental evidence that p50-p50 can inhibit the transactivating effects of p65-p50 and illustrates the potential for genetic modulation of inflammatory gene regulation in humans by subtle nucleotide changes that alter the relative binding affinities of different forms of the NF-kappa B complex.

* Corresponding author. Mailing address: Molecular Infectious Disease Group, Institute of Molecular Medicine, Oxford University, Oxford OX3 9DS, United Kingdom. Phone: 44-1865-222-345. Fax: 44-1865-222-626. E-mail: iudalova{at}molbiol.ox.ac.uk.

Molecular and Cellular Biology, December 2000, p. 9113-9119, Vol. 20, No. 24
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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