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Increased in vivo transcription of an IL-8 haplotype associated with respiratory syncytial virus disease-susceptibility

Genes & Immunity volume 5, pages 274–282 (2004)Cite this article

Abstract

Interleukin-8 (IL-8) has been implicated in the pathogenesis of RSV-induced bronchiolitis. Previously, we have described an association between bronchiolitis disease severity and a specific IL-8 haplotype comprising six single-nucleotide polymorphisms (SNPs) (−251A/+396G/+781T/+1238delA/+1633T/+2767T, haplotype 2). Here we investigated the functional basis for this association by measuring haplotype-specific transcription in vivo in human primary cells. We found a significant increase in transcript level derived from the IL-8 haplotype 2 relative to the mirror haplotype 1 (−251T/+396T/+781C/+1238insA/+1633C/+2767A) in respiratory epithelial cells but not in lymphocytes. A promoter polymorphism, −251A, present on the high producer haplotype, had no significant affect on the allele-specific level of transcription when analyzed in reporter gene experiments in human respiratory epithelial A549 cells. We proceeded to systematically screen for allele-specific protein-DNA binding in this functional haplotype, which revealed significant differential binding at the +781T/C polymorphism. C/EBP β was identified as being part of a transcription factor binding complex that preferentially bound in the presence of the +781 T allele. These results suggest that the mechanism for disease susceptibility to RSV-induced bronchiolitis may occur through a haplotype-specific increase in IL-8 transcription, which may be mediated by functional polymorphisms within that haplotype.

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Acknowledgements

We are grateful to the patients, anaesthetic and theatre staff of the John Radcliffe Hospital NHS Trust who assisted in the collection of the primary nasal cell cultures. This work was supported by grants from the Medical Research Council of the UK.

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Authors and Affiliations

  1. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK

    D Hacking, J C Knight, K Rockett, D P Kwiatkowski & I A Udalova

  2. Department of Paediatrics, University of Oxford, UK

    D Hacking, H Brown, D P Kwiatkowski & J Hull

  3. Department of Anatomy, The Medical School, Birmingham University, Edgbaston, Birmingham, UK

    J Frampton

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Correspondence to D Hacking.

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Hacking, D., Knight, J., Rockett, K. et al. Increased in vivo transcription of an IL-8 haplotype associated with respiratory syncytial virus disease-susceptibility. Genes Immun 5, 274–282 (2004). https://doi.org/10.1038/sj.gene.6364067

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