Cooperative influence of genetic polymorphisms on interleukin 6 transcriptional regulation

Interleukin 6 (IL6) plays key roles in hematopoiesis, immune, and acute pha se responses. Dysregulated IL6 expression is implicated in diseases such as atherosclerosis and arthritis. We have examined the functional effect of f our 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 t ranscriptional regulation in the ECV304 cell line compared with the HeLa ce ll line, suggesting cell type-specific regulation of IL6 expression. The ha plotypes showed functional differences in the ECV304 cell line; transcripti on 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 fun ctional; the base differences at distinct polymorphic sites do not act inde pendently of one another, and one polymorphism influences the functional ef fect of variation at other polymorphic sites. These results show that genet ic polymorphisms in the promoter influence IL6 transcription not by a simpl e additive mechanism but rather through complex interactions determined by the haplotype.