Abstract
IL-10 is known for its anti-inflammatory and regulatory function on different cell types involved in the pathogenesis of rheumatoid arthritis. Taking advantage of a stable intermediate phenotype (IL-10 induced by lipopolysaccharidestimulated blood cultures), large interindividual differences in IL-10 production were found. In two separate large studies including a total of > 50 twins, 70% of the variation between individuals could be explained by genetic factors. Differences in IL-10 protein production were present at the level of mRNA production, and analysis of the half-life of mRNA indicated that differences in transcription accounted for the interindividual differences. To test whether the different haplotypes were transcribed at a different rate, allele-specific transcript quantification was performed, and preliminary data indicated that some donors exhibited a 1:1 region of the respective mRNA species, and some donors a 1:1.2 ratio. To determine the length of the genomic region associated with different production of IL-10, eight single nucleotide polymorphisms (SNPs) and two CA repeats in the IL-10 gene, and six SNPs in the IL-10 homologues IL-19, IL-20 and IL-24 were analysed in 53 families in relation to IL-10 production. The preliminary data suggest that the region associated with differences in IL-10 production is a region of limited size around the IL-10 gene. Transient transfection assays of the -1413 to +31 fragments of the different haplotypes of the 5' region of the IL-10 gene in the myeloid cell lines U937 and Monomac6, in the B-cell line RAJI and in the T-cell line Jurkat showed no difference in promoter activity in response to stimulation for any of the haplotypes. However, a SNP outside this region, the -A2849G SNP, was associated with differences in IL-10 production. Next, a higher rate of joint destruction was observed in patients with the genotype associated with high IL-10 production (mean joint damage score of 20 vs 7; P < 0.001), most probably due to higher autoantibody titers in patients with the high IL-10 genotype.
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