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

Research output: Contribution to journalArticle

Authors

  • D Hacking
  • JC Knight
  • K Rockett
  • H Fox
  • DP Kwiatkowski
  • J Hull
  • IA Udalova

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 beta 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.

Details

Original languageEnglish
Pages (from-to)274-82
Number of pages9
JournalGenes and Immunity
Volume5
Early online date15 Apr 2004
Publication statusPublished - 15 Apr 2004

Keywords

  • lung, allele-specific expression, chemokines, human