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OC-048 Impact of the TLR4 Asp299gly polymorphism on induction of the inflammatory response following Helicobacter pylori infection
  1. K A Saunders,
  2. J C Crockett,
  3. S H Berry,
  4. E M El-Omar,
  5. G L Hold
  1. Department of Medicine and Dentistry, Aberdeen University, Aberdeen, UK

Abstract

Introduction The TLR4 Asp299Gly polymorphism causes immune dysregulation and is associated with unfavourable outcome in H pylori induced gastric cancer. It has been suggested that the polymorphism exerts effects through post-receptor signalling, more readily recruiting TRAM and inducing type I interferon production as opposed to Mal recruitment which activates NF-κB and pro-inflammatory cytokine production.

Methods Peripheral blood monocytes were isolated from individuals with and without the TLR4 Asp299Gly polymorphism. H pylori LPS was added to the cells and incubated for up to 6 h. RNA was extracted from monocytes and cDNA was synthesised and expression assessed in TLR4 signalling pathway genes. Activation of intermediate signalling steps in the Mal and TRAM pathways were assessed by western blot.

Results NF-κB gene expression in Asp299Gly polymorphism carriers was elevated after 2–4-h LPS stimulation compared to wildtype individuals. This delayed NF-κB gene expression in carriers of the polymorphism coincided with increased expression of components of the MyD88 independent pathway including IFN-β.

Conclusion The TLR4 Asp299Gly polymorphism influences downstream signalling and adaptor protein recruitment following LPS stimulation. Carriers of the polymorphism have increased expression of components of the Tram pathway. It is plausible that during H pylori infection, the TLR4 Asp299Gly polymorphism modulates LPS mediated inflammation which directly impacts on clinical outcome in H pylori infection.

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