TLR5 risk-associated haplotype for canine inflammatory bowel disease confers hyper-responsiveness to flagellin

Aarti Kathrani, Angela Holder, Brian Catchpole, Lorena Alvarez, Kenneth Simpson, Dirk Werling, Karin Allenspach

Research output: Contribution to journalArticle (Academic Journal)peer-review

43 Citations (Scopus)


Single nucleotide polymorphisms (SNP) in the TLR5 gene have been associated with human inflammatory bowel disease (IBD) and animal models of this disease. We recently demonstrated a significant association between three non-synonymous SNPs in the canine TLR5 gene and IBD in German shepherd dogs (GSDs). However, so far, no direct link between these SNPs and a disturbance in TLR5 function was shown. In the present study, we determined the functional significance of the canine TLR5 SNPs by transfecting the identified risk-protective and risk-associated haplotype into human embryonic kidney cells (HEK) and assessed nuclear factor-kappa B (NF-κB) activation and CXCL8 production after stimulation. In addition, a whole blood assay for TLR5 activation was developed using blood derived from carrier dogs of either haplotype. There was a significant increase in NF-kB activity when cells transfected with the risk-associated TLR5 haplotype were stimulated with flagellin compared to the cells expressing the risk-protective TLR5 haplotype. This difference in NFkB activation correlated with CXCL8 expression in the supernatant measured by ELISA. Furthermore, whole blood taken from carrier dogs of the risk-associated TLR5 haplotype produced significantly more TNF after stimulation with flagellin compared to that taken from carriers of the risk-protective haplotype. Thus, we show for the first time a direct functional impact of the canine IBD risk-associated TLR5 haplotype, which results in hyper-responsiveness to flagellin compared to the IBD risk-protective TLR5 haplotype. Our data potentially suggest that similarly to human IBD and experimental models, TLR5 may also play a role in canine IBD. Blocking the hyper-responsive receptor found in susceptible dogs with IBD may alleviate the inappropriate inflammation seen in this disease.

Original languageEnglish
Pages (from-to)e30117
JournalPLoS ONE
Issue number1
Publication statusPublished - 2012


  • Animals
  • Blood
  • Dogs
  • Flagellin
  • Genetic Predisposition to Disease
  • HEK293 Cells
  • Haplotypes
  • Humans
  • Inflammatory Bowel Diseases
  • Interleukin-8
  • Luminescent Proteins
  • Microscopy, Confocal
  • NF-kappa B
  • Polymorphism, Single Nucleotide
  • Risk Factors
  • Toll-Like Receptor 5
  • Tumor Necrosis Factor-alpha


Dive into the research topics of 'TLR5 risk-associated haplotype for canine inflammatory bowel disease confers hyper-responsiveness to flagellin'. Together they form a unique fingerprint.

Cite this