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Novel variants of the IL-10 receptor 1 affect inhibition of monocyte TNF-alpha production

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

  2. Author Address

    Gen Hosp Vienna, Dept Med 4, Wahringer Gurtel 18-20, A-1090 Vienna, Austria Univ Vienna, Dept Med 4, Div Gastroenterol & Hepatol, Vienna, Austria DNA Sci Inc, Fremont, CA 94555 USA NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA Univ London Imperial Coll Sci Technol & Med, Kennedy Inst Rheumatol, London, England Gasche C Gen Hosp Vienna, Dept Med 4, Wahringer Gurtel 18-20, A-1090 Vienna, Austria
    1. Year: 2003
  2. Journal: Journal of Immunology
    1. 170
    2. 11
    3. Pages: 5578-5582
  4. Type of Article: Article
  1. 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.

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