Differential regulation of interleukin-10 production by genetic and environmental factors--a twin study.
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 (-1082, -819 and -592) 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 -1082A allele showed higher binding affinity to the transcription factor PU.1 resulting in decreased transcriptional activity of -1082A 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 -1082A 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.
Reuss
E
E
Department of Internal Medicine, Johannes Gutenberg-University, Mainz, Germany.
Fimmers
R
R
Kruger
A
A
Becker
C
C
Rittner
C
C
Höhler
T
T
D001665:Binding Sites / Q000235:genetics; D002460:Cell Line; D004247:DNA / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D017930:Genes, Reporter; D006801:Humans; D066298:In Vitro Techniques; D016753:Interleukin-10 / Q000096:biosynthesis / Q000235:genetics*; D008297:Male; D009000:Monocytes / Q000502:physiology; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000378:metabolism; D018433:Twin Studies as Topic
D014157:Transcription Factors; D016753:Interleukin-10; D004247:DNA