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

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 intestin...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2003-06, Vol.170 (11), p.5578-5582
Main Authors: Gasche, Christoph, Grundtner, Paul, Zwirn, Petra, Reinisch, Walter, Shaw, Sarah H, Zdanov, Alexander, Sarma, Usha, Williams, Lynn M, Foxwell, Brian M, Gangl, Alfred
Format: Article
Language:English
Subjects:
Amino Acid Substitution - genetics
Amino Acid Substitution - immunology
Arginine - genetics
Crohn Disease - genetics
Crohn Disease - immunology
DNA, Complementary - analysis
Gene Frequency - immunology
Genetic Variation - immunology
Genotype
Glycine - genetics
Haplotypes - immunology
Humans
Interleukin-10 - metabolism
Macromolecular Substances
Models, Molecular
Monocytes - immunology
Monocytes - metabolism
Polymorphism, Single Nucleotide - immunology
Receptors, Interleukin - biosynthesis
Receptors, Interleukin - chemistry
Receptors, Interleukin - genetics
Receptors, Interleukin - physiology
Receptors, Interleukin-10
Serine - genetics
Tumor Necrosis Factor-alpha - antagonists & inhibitors
Tumor Necrosis Factor-alpha - biosynthesis
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Summary: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.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.170.11.5578