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

• Published in: Genes and immunity Vol. 10; no. 4; pp. 341 - 349
• Main Authors: Early, S B, Huyett, P, Brown-Steinke, K, Borish, L, Steinke, J W
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.06.2009; Nature Publishing Group
• Subjects: Alleles; Asthma; Atopy; Biomedical and Life Sciences; Biomedicine; Cancer Research; CD4 antigen; Cell lines; Chromatin; Drug therapy; Gene Expression; Gene polymorphism; Health aspects; Human Genetics; Immunology; Immunomodulation; Immunoprecipitation; Interleukin 9; Lymphocytes T; NF-κB protein; Nucleotide sequence; original-article; Polymorphism; Protein binding; T cells; cytokine; polymorphism; functional genomics; interleukin-9; transcription
• ISSN: 1466-4879; 1476-5470
• DOI: 10.1038/gene.2009.28

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.