IL10 Promoter Polymorphisms and IL10 Production

IL-10 production is regulated at the transcriptional level, and studies suggest that heritable genetic differences that associate with inter-individual differences in gene expression may differentially regulate IL-10 production.19-21 There is also evidence that suggests the existence of post-transcriptional regulation by RNA-destabilizing, AU-rich elements within the 3 -untranslated of IL-10 mRNA.22

Inter-individual differences in IL-10 production is heritable.23 First degree relatives of SLE patients produce high levels of IL-10 compared with unrelated controls,24 and first-degree relatives of nonsurvivors of fatal meningococcal disease produce significantly lower levels of IL-10 than relatives of survivors.23,25 The implication of a heritable genetic basis for IL-10 production is also supported by the concordance of IL-10 production in monozygotic twins, which suggests that genetics could account for up to 75% of IL-10 production. 3 Therefore, high IL-10 production associated with autoimmune diseases may represent a risk factor for disease susceptibility or severity, and the genetic polymorphisms that regulate IL-10 production represent genetic risk factors for autoimmune diseases.1'9'10'18'19'24'2

Promoter-reporter studies have identified several positive and negative regulatory promoter sequences within the 1.3 kb region upstream of the transcription start site, and a transcription factor binding site search of the immediate 4kb promoter region has identified more than 74 potential binding sites.27,28 Three functional NF-kB and a Stat3 binding site, and four cAMP-responsive elements have been identified in the 2kb promoter region of the human IL-10 promoter.29-31 However, none of these elements appear to be polymorphic. Functional Sp1 and Sp3 transcription factor binding sites have similarly been identified in the murine IL-10 promoter.32

Il10 Promoter

Figure 1. Schematic representation of the IL-10 promoter region: A) SNPs identified within putative transcription factor binding sites using the TESS search tool (http://www.cbil.upenn.edu/tess/); B) Novel SNPs identified in the distal promoter (AWG, unpublished results); C) Additional identified SNPs not lying in currently recognized transcription factor binding sites.

Figure 1. Schematic representation of the IL-10 promoter region: A) SNPs identified within putative transcription factor binding sites using the TESS search tool (http://www.cbil.upenn.edu/tess/); B) Novel SNPs identified in the distal promoter (AWG, unpublished results); C) Additional identified SNPs not lying in currently recognized transcription factor binding sites.

The human IL-10 promoter is highly polymorphic. Two (CA) short tandem repeat polymorphisms (STRP), IL-10.R and IL-10.G, have been identified at -4 kb and -1.1 kb, respectively, and three single nucleotide polymorphisms (SNP), -1082G/A, -819C/T and -597C/A, which form three predominant haplotypes (GCC, ACC, ATA), had been identified previously in the 1.0 kb promoter region.33-36 A fourth haplotype, GTA, was seen only in a Chinese population.37 The G allele at -1082 and haplotypes containing this allele have been associated with high IL-10 production, while the A allele and the ATA haplotype have been associated with low IL-10 production.35,38

Resequencing within the 8kb promoter region by various groups has identified at least 23 additional SNPs (Fig. 1),19,39,40 and four novel SNPs have been identified recently in the 3' untranslated region (3' UTR).41 Significant differences in the allele frequencies of some promoter SNPs have been seen in different ethnic or geographic populations, underscoring the need for appropriate stratification in disease association studies (Table 1).42 Haplotypes defined by proximal and distal SNPs19,35,43 and by SNPs and STRP alleles associate with IL-10 production.39,44 However, because of variable, inconsistent associations between IL-10 production and different SNP alleles, SNP haplotypes and STRP alleles, it is currently unclear which promoter polymorphisms are causal in determining differences in IL-10 production. Data from our group, which showed an association between distal SNP haplotypes and IL-10 production suggest that SNPs in the distal promoter may play a role in IL-10 production.19

Was this article helpful?

0 0
Natural Treatments For Psoriasis

Natural Treatments For Psoriasis

Do You Suffer From the Itching and Scaling of Psoriasis? Or the Chronic Agony of Psoriatic Arthritis? If so you are not ALONE! A whopping three percent of the world’s populations suffer from either condition! An incredible 56 million working hours are lost every year by psoriasis sufferers according to the National Psoriasis Foundation.

Get My Free Ebook


Post a comment