Differential regulation of interleukin-10 production by genetic and environmental factors – a twin study

Abstract

Interleukin-10 (IL-10) has a critical role in the regulation of immune responses. The relative contribution of genetic and environmental factors to IL-10 production is under debate. We performed a twin study in 246 monozygotic and dizygotic twins to assess the heritability of IL-10 production after LPS stimulation in whole blood. In addition, the influence of promoter single nucleotide polymorphisms (À1082, À819 and À592) on transcriptional activity and their binding to nuclear factors was studied in luciferase reporter gene and electrophoretic mobility shift assays. IL-10 production showed a genetic determination with a heritability of 0.5. Decreasing body mass index (BMI), smoking and female gender lead to decreased IL-10 production. In monocytes, the À1082A allele showed higher binding affinity to the transcription factor PU.1 resulting in decreased transcriptional activity of À1082A promoter haplotypes. Genetic determination of IL-10 secretion is probably lower than that previously reported. Fifty percent of the observed variability explained by genetic factors. Female individuals produce less IL-10 than male subjects. Environmental factors like smoking and decreasing BMI exert suppressing effects on IL-10 production. Although the À1082A allele shows higher binding affinity to the PU.1 transcription factor and lower transcriptional activity, this polymorphism probably explains only a small fraction of the observed heritability.

Promoter haplotypes of the interleukin-10 gene influence proliferation of peripheral blood cells in response to helminth antigen

“…Whereas the genetic influence on LPS-induced IL-10 production was estimated to explain a proportion of variance of 0.5 and a heritability of 0.75, 10,28 we found a proportion of variance explained (r 2 of QTDT) as small as 0.02 for the influence of the ATA haplotype on antigen-reactive proliferation. The reason may well be that, in contrast to the direct effect of LPS on macrophages, the effect of an antigen on IL-10 production by T cells is influenced by a number of variables, including antigen presentation, costimulatory activities, numbers of antigen-reactive Tr1 cells, and possible influences of concomitant infections.…”

Host genetic determinants in hepatitis C virus infection

“…24 A recent paper suggested that the production of IL10 is probably more complicated than originally thought, as environmental factors may work along with genetic factors to play a role in affecting IL10 expression. 86 This complexity underlying IL10 expression may explain some of the discrepancies between these studies. A couple of studies have examined the role of TNF variants and the response to therapy.…”

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 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. 26,27 Recently, we reported that the PU.1, Spi-B and Sp1transcription factors bound to the À1087 SNP in Bcells.…”

“…[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. 26,27 Recently, we reported that the PU.1, Spi-B and Sp1transcription factors bound to the À1087 SNP in Bcells. 28 Although PU.1 and Spi-B bound to both the G and A allele, Sp1 bound only to the G allele and thereby promoted an increase in promoter activity.…”