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Novel variants of the il-10 receptor 1 affect inhibition of monocyte tnf-alpha production

Academic Article
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Overview

authors

  • Gasche, C.
  • Grundtner, P.
  • Zwirn, P.
  • Reinisch, W.
  • Shaw, S. H.
  • Zdanov, A.
  • Sarma, U.
  • Williams, L. M.
  • Foxwell, B. M.
  • Gangl, A.

publication date

  • June 2003

journal

  • Journal of Immunology  Journal

abstract

  • IL-10-deficient mice exhibit spontaneous enterocolitis and other symptoms akin to Crohn's disease, indicating that IL-10 might regulate normal physiology in the gut. However, clinical trials with IL-10 in Crohn's disease were disappointing, although some patients showed healing of intestinal mucosa. This study searched for genetic polymorphisms within the IL-10 pathway. We decided to screen for mutations of the IL-10R1 cDNA in healthy volunteers and Crohn's disease patients and identified two novel variants: a serine 138-to-glycine (S138G) and a glycine 330-to-arginine (G330R) substitution. The allelic frequency in a European cohort was relatively high (16% for the S138G and 33% for the G330R), and S138G was in strong linkage disequilibrium with G330R. A similar allele frequency was found in a group of Crohn's patients. In IL-10R1 G330R-expressing monocytes, the inhibitory effect of IL-10 on TNF-alpha production was diminished, indicating that this variant may be a loss-of-function allele. No such difference was observed between haplotypes 4 (G330R only) and 7 (S138G and G330R). In addition, these IL-10R1 variants had no influence on the IL-10R1 expression density. Structural analysis of the S138G variant revealed that the substitution of S138G may interfere with binding of IL-10 to IL-10R1.

subject areas

  • Amino Acid Substitution
  • Arginine
  • Crohn Disease
  • DNA, Complementary
  • Gene Frequency
  • Genetic Variation
  • Genotype
  • Glycine
  • Haplotypes
  • Humans
  • Interleukin-10
  • Macromolecular Substances
  • Models, Molecular
  • Monocytes
  • Polymorphism, Single Nucleotide
  • Receptors, Interleukin
  • Receptors, Interleukin-10
  • Serine
  • Tumor Necrosis Factor-alpha
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Identity

International Standard Serial Number (ISSN)

  • 0022-1767

PubMed ID

  • 12759436
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Additional Document Info

start page

  • 5578

end page

  • 5582

volume

  • 170

issue

  • 11

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