Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation
Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation
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DOI：
10.1073/pnas.94.7.3195
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发表时间：
1997-04-01
影响因子：
11.1
通讯作者：
Duff, GW
中科院分区：
文献类型：
--
作者：
Wilson, AG;Symons, JA;Duff, GW
肿瘤坏死因子α（TNF α）是一种有效的免疫调节剂和促炎细胞因子，其与自身免疫性疾病和感染性疾病的发病机制有关。例如，TNF α的血浆水平与疟疾和利什曼病的严重程度和死亡率正相关。我们先前描述了TNF α启动子中-308处的多态性，并表明罕见等位基因TNF 2位于扩展单倍型HLA-A1-B8-DR 3-DQ 2上，其与自身免疫和高TNF α产生相关，TNF 2的纯合性使脑型疟疾的死亡风险增加7倍。在此，我们证明，在人B细胞系中，在两个等位基因TNF启动子的控制下，TNF 2是比常见等位基因（TNF 1）强得多的转录激活因子，使用DNA酶I和B细胞核提取物的足迹分析显示在-308和邻近保护区处产生超敏位点。两个等位基因之间的DNA结合蛋白的亲和力没有差异，这些结果表明，该多态性对TNF α基因调控有直接影响，并可能与TNF 2与高TNF α相关表型和更严重的疾病感染，如疟疾和利什曼病。
Tumor necrosis factor alpha (TNF alpha) is a potent immunomodulator and proinflammatory cytokine that has been implicated in the pathogenesis of autoimmune and infectious diseases. For example, plasma levels of TNF alpha are positively correlated with severity and mortality in malaria and leishmaniasis, We have previously described a polymorphism at -308 in the TNF alpha promoter and shown that the rare allele, TNF2, lies on the extended haplotype HLA-A1-B8-DR3-DQ2, which is associated with autoimmunity and high TNF alpha production, Homozygosity for TNF2 carries a sevenfold increased risk of death from cerebral malaria, Here we demonstrate, with reporter genes under the control of the two allelic TNF promoters, that TNF2 is a much stronger transcriptional activator than the common allele (TNF1) in a human B cell line, Footprint analysis using DNase I and B cell nuclear extract showed the generation of a hypersensitive site at -308 and an adjacent area of protection, There was no difference in affinity of the DNA-binding protein(s) between the two alleles, These results show that this polymorphism has direct effects on TNF alpha gene regulation and may be responsible for the association of TNF2 with high TNF alpha phenotype and more severe disease in infections such as malaria and leishmaniasis.