Cooperative Influence of Genetic Polymorphisms on Interleukin 6 Transcriptional Regulation*
- From the ‡Nuffield Department of Surgery, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DU, United Kingdom and §INSERM SC7, 17 rue du Fer a Moulin, 75005 Paris, France
Abstract
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, −373AnTn, −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.
Footnotes
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↵* This work was supported by the Medical Research Council and British Heart Foundation Grant SF/95024.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵¶ To whom correspondence should be addressed. Current address: BHF Molecular Cardiology Laboratory, Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Headington, Oxford OX3 7BN, United Kingdom. Fax: 44-1865-287664; E-mail: fionag@well.ox.ac.uk.
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Published, JBC Papers in Press, March 22, 2000, DOI 10.1074/jbc.M000379200
- Abbreviations:
- IL
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interleukin
- PCR
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polymerase chain reaction
- CAT
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chloramphenicol acetyltransferase
- CMV
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cytomegalovirus
- TNFα
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tumor necrosis factor α
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- Received January 19, 2000.
- Revision received March 20, 2000.
- The American Society for Biochemistry and Molecular Biology, Inc.
