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 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.
Gasche
Christoph
C
Department of Medicine 4, Division of Gastroenterology and Hepatology, University of Vienna, Vienna, Austria. christoph.gasche@akh-wien.ac.at
Grundtner
Paul
P
Zwirn
Petra
P
Reinisch
Walter
W
Shaw
Sarah H
SH
Zdanov
Alexander
A
Sarma
Usha
U
Williams
Lynn M
LM
Foxwell
Brian M
BM
Gangl
Alfred
A
D019943:Amino Acid Substitution / Q000235:genetics / Q000276:immunology; D001120:Arginine / Q000235:genetics; D003424:Crohn Disease / Q000235:genetics / Q000276:immunology; D018076:DNA, Complementary / Q000032:analysis; D005787:Gene Frequency / Q000276:immunology; D014644:Genetic Variation / Q000276:immunology*; D005838:Genotype; D005998:Glycine / Q000235:genetics; D006239:Haplotypes / Q000276:immunology; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism*; D046911:Macromolecular Substances; D008958:Models, Molecular; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide / Q000276:immunology; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000737:chemistry* / Q000235:genetics* / Q000502:physiology; D053701:Receptors, Interleukin-10; D012694:Serine / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*
D018076:DNA, Complementary; D046911:Macromolecular Substances; D018123:Receptors, Interleukin; D053701:Receptors, Interleukin-10; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D012694:Serine; D001120:Arginine; D005998:Glycine