Functional analysis of -571 IL-10 promoter polymorphism reveals a repressor element controlled by sp1.
Transcriptional dysregulation of the IL-10 gene may contribute to the development and severity of autoimmune, infectious, neoplastic, and allergic diseases. A C to A base substitution has been identified at -571 bp in the IL-10 promoter and has been linked to immune diseases. The role of this polymorphism in IL-10 promoter function was assessed using luciferase reporter constructs. The presence of an A at -571 (A allele) increases promoter activity compared with that of a promoter with a C at this position (C allele). Binding of nuclear extract proteins from IL-10-producing human cell lines to DNA sequences including this base exchange and flanking sequences was demonstrated using EMSAs. Specific binding of the transcription factors Sp1 and Sp3 was demonstrated to a region immediately upstream of the polymorphism. No differences in the binding affinity of recombinant Sp1 were observed between the two forms of the promoter. Reconstitution of Sp1 expression decreased IL-10 promoter function in an Sp1-deficient cell line, demonstrating that this element functions as a repressor. The C to A base exchange relieves the repression mediated by Sp1. Individuals carrying the A allele of the IL-10 promoter may display increased synthesis of IL-10, resulting in suppressed immune responses and a modulation of their susceptibility to autoimmune, infectious, neoplastic, or atopic disease.
Asthma and Allergic Diseases Center, Beirne Carter Center for Immunology Research, University of Virginia, Charlottesville, VA 22908, USA. js3ch@virginia.edu
John W
JW
Steinke
Elizabeth
E
Barekzi
James
J
Hagman
Larry
L
Borish
D001402:B-Lymphocytes / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics*; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D051705:Sp3 Transcription Factor; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology
D004268:DNA-Binding Proteins; C497121:SP3 protein, human; D016329:Sp1 Transcription Factor; D014157:Transcription Factors; D016753:Interleukin-10; D051705:Sp3 Transcription Factor