Functional analysis of -351 interleukin-9 promoter polymorphism reveals an activator controlled by NF-kappaB.
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-kappaB. Binding of NF-kappaB to the IL-9 promoter was confirmed in vivo using the chromatin immunoprecipitation assay. Recombinant NF-kappaB 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.
Early
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SB
Asthma and Allergic Diseases Center, Beirne Carter Center for Immunology Research, University of Virginia, Charlottesville, VA 22908-1355, USA.
Huyett
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P
Brown-Steinke
K
K
Borish
L
L
Steinke
J W
JW
D000293:Adolescent; D000328:Adult; D000483:Alleles; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D005786:Gene Expression Regulation; D006801:Humans; D016906:Interleukin-9 / Q000235:genetics* / Q000276:immunology; D019169:Jurkat Cells; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism*; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000502:physiology; D011994:Recombinant Proteins / Q000378:metabolism; D055815:Young Adult
D016906:Interleukin-9; D016328:NF-kappa B; D011994:Recombinant Proteins