The interleukin-10 - 1082 G/A polymorphism: allele frequency in different populations and functional significance

Abstract

Genotypic variation in the human interleukin-10 (IL-10) promoter may account for marked inter-individual variation in IL-10 production and may influence susceptibility to autoimmune diseases. The G/A polymorphism at position -1082 has been linked to high/low IL-10 producer status. We directly tested the functional significance of this polymorphism using DNA-binding assays and reporter gene assays, examined allele frequencies in two geographically distinct populations and assessed intra- and inter-individual variation in IL-10 production in vitro according to genotype. Functional analyses showed that the -1082 region contains a putative ETS-like transcription factor-binding site, and nuclear factors from a monocyte cell line bind to this region. Transient transfection studies in an Epstein-Barr virus-transformed B cell line indicated that the -1082 A allele confers a two fold increase in transcriptional activity of the IL-10 promoter compared to the G allele. There was marked inter-individual variation in IL-10 production by peripheral blood mononuclear cells in vitro, with no consistent effect of genotype.

Sp1 binds to the G allele of the−1087 polymorphism in the IL-10 promoter and promotes IL-10 mRNA transcription and protein production

“…19,20,26,27,32 The present series of experiments were performed to study the influence of the binding of the Sp1 transcription factor to the À1087 SNP on IL-10 transcription. The binding of the transcription factors PU.1, Spi-B and Sp1 to this site in the IL-10 promoter was earlier analyzed using electromobility shift assay.…”

“…19,[25][26][27]32,40,41 Thus, Turner et al 27 found that subjects who were negative for the A allele exhibited a higher production of IL-10 than subjects who were positive for the A allele. These results are in concordance with data presented in a study on stimulated purified blood lymphocytes.…”

“…17,18 Owing to large inter-individual variations in IL-10 production, a possible genetic influence on the regulation of this cytokine was suggested. 19,20 Changes in the IL-10 gene expression were suggested to be mainly transcriptional and several factor-binding sites that might be involved in the regulation of IL-10 were identified in the IL-10 promoter. [21][22][23][24] The À1087 single nucleotide polymorphism (SNP) is located in one of these sites that was associated with differences in IL-10 gene expression [25][26][27] and the GG genotype of the À1087 SNP was found to be associated with high levels of IL-10 production.…”

The Sp1 transcription factor binds to the G-allele of the –1087 IL-10 gene polymorphism and enhances transcriptional activation

“…Thus, the presence of an A-allele was shown to result in an increase in the IL-10 promoter activity, which may lead to enhanced production of the IL-10 protein. 23 Conversely, other reports suggested that the presence of a G-allele at À1087 was associated with an increase in the IL-10 promoter activity. 24,25,28,29 In earlier studies from our laboratory, 30,31 we demonstrated that severe chronic periodontitis was strongly associated with the GG genotype of the À1087 IL-10 gene polymorphism and that the GG genotype correlated with enhanced fractions of IL-10-positive cells in periodontitis lesions.…”

“…[20][21][22] The IL-10 promoter contains several single nucleotide polymorphisms (SNPs) among which the -1087 G/A SNP (sometimes referred to as À1082 G/A) was associated with differences in IL-10 promoter activity and IL-10 production. [23][24][25][26][27][28][29] Results of studies on the influence of the -1087 SNP on the IL-10 production in different cell types, 23,[25][26][27][28][29] however, are conflicting. Thus, the presence of an A-allele was shown to result in an increase in the IL-10 promoter activity, which may lead to enhanced production of the IL-10 protein.…”