Cooperative influence of genetic polymorphisms on interleukin 6 transcriptional regulation
Cooperative influence of genetic polymorphisms on interleukin 6 transcriptional regulation
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DOI：
10.1074/jbc.m000379200
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发表时间：
2000-06-16
影响因子：
4.8
通讯作者：
Green, FR
中科院分区：
文献类型：
--
作者：
Terry, CF;Loukaci, V;Green, FR
白细胞介素6 （IL6）在造血、免疫和急性期反应中起关键作用。il - 6表达失调与动脉粥样硬化和关节炎等疾病有关。我们通过鉴定自然发生的单倍型并比较它们对报告基因表达的影响，研究了il - 6启动子(-597G- >A, -572G- >C, -373A（n)T(n), -174G- >C）的四种多态性的功能影响。结果表明，与HeLa细胞系相比，ECV304细胞系的转录调控存在差异，提示il - 6的表达存在细胞特异性调控。单倍型在ECV304细胞系中存在功能差异；GG9/11G单倍型的转录率较高，AG8/12G等位基因的转录率较低。这些差异表明不止一个多态位点是功能性的；不同多态性位点上的碱基差异并不是相互独立的，一个多态性会影响其他多态性位点变异的功能效应。这些结果表明，启动子的遗传多态性影响IL6转录不是通过简单的加性机制，而是通过单倍型决定的复杂相互作用。
Interleukin 6 (IL6) plays key roles in hematopoiesis, immune, and acute phase responses. Dysregulated IL6 expression is implicated in diseases such as atherosclerosis and arthritis. We have examined the functional effect of four polymorphisms in the IL6 promoter (-597G-->A, -572G-->C, -373A(n)T(n), -174G-->C) by identifying the naturally occurring haplotypes and comparing their effects on reporter gene expression. The results indicate different transcriptional regulation in the ECV304 cell line compared with the HeLa cell line, suggesting cell type-specific regulation of IL6 expression. The haplotypes showed functional differences in the ECV304 cell line; transcription was higher from the GG9/11G haplotype and lower from the AG8/12G allele. The differences suggest that more than one of the polymorphic sites is functional; the base differences at distinct polymorphic sites do not act independently of one another, and one polymorphism influences the functional effect of variation at other polymorphic sites. These results show that genetic polymorphisms in the promoter influence IL6 transcription not by a simple additive mechanism but rather through complex interactions determined by the haplotype.