Functional Analysis of −571 IL-10 Promoter Polymorphism Reveals a Repressor Element Controlled by Sp1

Steinke, John W.; Barekzi, Elizabeth; Hagman, James; Borish, Larry

doi:10.4049/jimmunol.173.5.3215

Cited by 61 publications

(41 citation statements)

References 63 publications

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“…The -571 base exchange occurs between what we confirmed as being an Sp family member binding site and a sequence with similarity to that recognized by members of the ets family (AGGAA) [19]. The transcription factor(s) that specifically binds to this region of the IL-10 promoter has not yet been identified, however, the binding affinity of this factor was influenced by the C-to-A base exchange (unpublished data).…”

Section: Discussionsupporting

confidence: 61%

“…Specifically, it has been demonstrated that the C-to-A nucleotide exchange at position -571 results in increased promoter activity in B cells and that the transcription factors Sp1 and Sp3 can bind to a region immediately upstream of the polymorphism. The region including the Sp1/Sp3 site and adjoining polymorphism functions as a transcriptional repressor, and the Cto-A base exchange relieves the repression mediated by Sp1 [19]. We demonstrated that the A allele was associated with elevated total serum IgE in subjects heterozygotic or homozygotic for this base exchange [20].…”

Section: Introductionmentioning

confidence: 81%

“…Sp1 is a ubiquitous factor that is important in both transcriptional activation and repression. The interaction of Sp1/Sp3 with this region of the IL-10 promoter was associated with decreased promoter function [19]. A variety of transcription factors would be activated following stimulation of cells and action through different signaling cascades.…”

Section: Discussionmentioning

confidence: 99%

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Differential interleukin-10 production stratified by −571 promoter polymorphism in purified human immune cells

Steinke¹,

Barekzi²,

Huyett³

et al. 2007

Cellular Immunology

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SummaryA C-to-A base substitution has been identified at bp -571 in the IL-10 promoter and has been linked to numerous diseases. To investigate the role of this polymorphism on IL-10 production, T cells, B cells and monocytes were enriched from peripheral blood from subjects either homozygous for the C or A allele. Treatment of monocytes and B cells with lipopolysaccharide from individuals homozygous for the C allele resulted in higher levels of IL-10 production as compared to monocytes from individuals homozygous for the A allele. Though not statistically significant, when B cells were treated with anti-IgM or T cells with concanavalin A higher levels of IL-10 were produced from individuals homozygous for the A allele. Changes in IL-10 protein production were paralleled by similar changes in IL-10 mRNA production. These results demonstrate that changes in IL-10 production observed due to the -571 genotype depend on both cell type and stimulus.

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Section: Discussionsupporting

confidence: 61%

Section: Introductionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

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Differential interleukin-10 production stratified by −571 promoter polymorphism in purified human immune cells

Steinke¹,

Barekzi²,

Huyett³

et al. 2007

Cellular Immunology

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“…38 LPS activates the three mitogen-activated protein kinase (MAPK9) pathways ERK, JNK and p38 and, thereby, transcription factors that are involved in gene regulation. 35 Chanteux et al 35 showed that ERK, p38, JNK as well as Sp1 are essential in LPS-induced IL-10 expression in human alveolar macrophages.…”

Section: Discussionmentioning

confidence: 99%

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

2010

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Interleukin (IL)-10 is an important cytokine in immune regulation and promotes B-cell proliferation and antibody production. High levels of IL-10 were found in subjects with autoimmune diseases. The A to G single nucleotide polymorphism at -1087 of the IL-10 promoter is associated with differences in promoter activity and IL-10 production. The objectives of this study were to analyze differences in the transcription factor binding to the -1087 IL-10 gene polymorphism in B-cells, the influence of the A to G transition on the IL-10 and Sp1 gene expression in B-cells after lipopolysaccharide (LPS) stimulation and the effect of knockdown of Sp1 on IL-10 gene expression. Using B-cell lines obtained from subjects with GG and AA genotypes for the À1087 polymorphism and chromatin immunoprecipitation assay, we showed that the transcription factors PU.1 and Spi-B bound to both G and A alleles, whereas the transcription factor Sp1 only bound to the G allele. LPS stimulation of the B-cells resulted in a larger increase in IL-10 and Sp1 gene expression for GG genotypes than AA genotypes and knockdown of Sp1 gene expression resulted in a decrease in IL-10 mRNA transcription. IL-10 production was higher for the GG genotype than for the AA genotype.

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“…33 This binding site is present in both reporter plasmids, GCC and ACC. DG75 B cells were transfected with the GCC and ACC reporter plasmids and subsequently incubated with or without LPS.…”

Section: Sp1 Transcription Factor Binds To the Il-10 à1087 G-allele Lmentioning

confidence: 98%

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

et al. 2008

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The objectives of this study were to evaluate the influence of the À1087 single nucleotide polymorphism (SNP) on the gene expression of interleukin (IL)-10 and to identify transcription factors binding to this site in B cells. Using electrophoretic mobilityshift assays and nuclear extract from the DG75 B-cell line, we demonstrated that the Sp1 transcription factor bound to the À1087 G-allele of the IL-10 promoter and that the transcription factors PU.1 and Spi-B bound to both the G-and A-alleles. Transient transfections showed that lipopolysaccharide stimulation resulted in a 15-fold increase in promoter activity for the G-allele as compared to a 6-fold increase for the A-allele. Co-transfection with Sp1 expression vector in Sp1-deficient SL2 cells leading to Sp1 binding to the G-allele of the À1087 SNP resulted in increased IL-10 promoter activity. The results suggest a role for Sp1 transcription factor in the activation of IL-10 through the G-allele of the À1087 SNP in response to inflammatory signals.

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Functional Analysis of −571 IL-10 Promoter Polymorphism Reveals a Repressor Element Controlled by Sp1

Cited by 61 publications

References 63 publications

Differential interleukin-10 production stratified by −571 promoter polymorphism in purified human immune cells

Differential interleukin-10 production stratified by −571 promoter polymorphism in purified human immune cells

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

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

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