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Functional analysis of −351 interleukin-9 promoter polymorphism reveals an activator controlled by NF-κB

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Abstract

Genetic studies have shown linkages for asthma to the chromosomal region 5q31–q33 in humans that includes the IL-9 gene. An A-to-G base substitution has been identified at bp −351 in the IL-9 promoter. The role of this polymorphism in IL-9 promoter function was assessed utilizing CD4+ T cells purified from individuals with one or two of the G alleles in comparison to those homozygous for the wild-type A. The presence of an A at –351 (A allele) increased mitogen-stimulated IL-9 transcription twofold in comparison to subjects with one or two G alleles at this position. Binding of nuclear extract proteins from IL-9-producing human cell lines to DNA sequences including this base exchange demonstrated specific binding of the transcription factor NF-κB. Binding of NF-κB to the IL-9 promoter was confirmed in vivo using the chromatin immunoprecipitation assay. Recombinant NF-κB bound to a promoter fragment with the A allele with fivefold higher affinity than it did to a promoter with the G allele. Individuals carrying the A allele of the IL-9 promoter display increased synthesis of IL-9, which may result in strong Th2 immune responses and a modulation of their susceptibility to infectious, neoplastic, parasitic or atopic disease.

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Acknowledgements

This work was supported by NIH AI01793.

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Authors and Affiliations

  1. Asthma and Allergic Diseases Center, Beirne Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, USA

    S B Early, P Huyett, K Brown-Steinke, L Borish & J W Steinke

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  1. S B Early
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  2. P Huyett
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  3. K Brown-Steinke
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Correspondence to J W Steinke.

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Early, S., Huyett, P., Brown-Steinke, K. et al. Functional analysis of −351 interleukin-9 promoter polymorphism reveals an activator controlled by NF-κB. Genes Immun 10, 341–349 (2009). https://doi.org/10.1038/gene.2009.28

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  • DOI: https://doi.org/10.1038/gene.2009.28

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