Article Text

PDF

18 TILRR Functional Mutants Selectively Inhibit Inflammatory and Anti-Apoptotic Responses
  1. M Neilan1,
  2. X Zhang1,
  3. T Steiner1,
  4. J Boyle2,
  5. S Francis1,
  6. D Haskard2,
  7. E Qwarnstrom1
  1. 1Cardiovascular Science, University of Sheffield, UK
  2. 2Vascular Sciences, National Heart and Lung Inst., Imperial College London, UK

Abstract

Toll-like and IL-1 receptors control inflammatory responses. TILRR (Toll-like IL-1 Receptor Regulator), is an IL-1 co-receptor which associates with the type I IL-1 receptor (IL-1RI) to amplify activation of NF-kappaB and inflammatory responses. Earlier studies have demonstrated increased levels of TILRR in the atherosclerotic plaque. Further, that injection of a polyclonal anti-TILRR antibody, which blocks TILRR/IL-1RI association and reduces inflammatory responses, causes a 25% decrease in plaque formation in ApoE-/- mice on a high fat diet. Alanine scanning mutagenesis identified two sites within the TILRR core protein, which allow distinct control of Il-1 activities. The R425A substitution blocks enhanced cell survival, but functions as wild-type in relation to inflammatory responses. In contrast, a D448A substitution reduces MyD88-dependent inflammatory responses, but has no impact on cell survival [1]. Current studies use peptides designed to block these distinct functional sites to further analyse consequences of selective inhibition on downstream events. Results show a successive reduction in inflammatory responses by the peptide designed to block D448 dependent interactions, with no effect of the peptide targeting anti-apoptotic signals or a non-specific control. Ongoing studies are testing the effect of the peptides on IL-1-induced cell survival.

1. Zhang, X., et al., JBC, 2012, doi:10.1074/jbc.C111.321711

Statistics from Altmetric.com

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.