Functional analysis of -351 interleukin-9 promoter polymorphism reveals an activator controlled by NF-kappaB.
Functional analysis of -351 interleukin-9 promoter polymorphism reveals an activator controlled by NF-kappaB.
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DOI：
10.1038/gene.2009.28
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发表时间：
2009-06
影响因子：
5
通讯作者：
Steinke, J. W.
中科院分区：
文献类型：
--
作者：
Early, S. B.;Huyett, P.;Brown-Steinke, K.;Borish, L.;Steinke, J. W.
遗传学研究表明，哮喘与人类染色体5q31-q33区域有关，其中包括IL-9基因。在IL-9启动子的bp -351处发现了A-to-G碱基取代。这种多态性在IL-9启动子功能中的作用是利用从具有一个或两个G等位基因的个体中纯化的CD4+ T细胞来评估的，与野生型A的纯合子相比，-351 （A等位基因）的A的存在使有丝分裂原刺激的IL-9转录增加了2倍，与在该位置具有一个或两个G等位基因的受试者相比。从产生il -9的人类细胞系中提取的核提取物蛋白与DNA序列的结合，包括这种碱基交换，证明了转录因子NF-κB的特异性结合。利用染色质免疫沉淀法在体内证实了NF-κB与IL-9启动子的结合。重组NF-κB与a等位基因启动子片段结合的亲和力比与G等位基因启动子片段高5倍。携带IL-9启动子A等位基因的个体显示IL-9合成增加，这可能导致强烈的Th2免疫反应，并调节其对感染性、肿瘤性、寄生虫性或特应性疾病的易感性。
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 2-fold in comparison to subjects with one or 2 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 5 fold 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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