T helper type-2 (Th2) immunity orchestrates responses against extracellular pathogens under normal conditions and mediates pathogenic responses against innocuous substances when dysregulated, leading to allergic disease. Among the cytokines expressed by Th2 cells, interleukin (IL)-13 has emerged as a critical effector molecule in Th2 responses and common IL13 variants are associated with allergy-related phenotypes in populations of distinct ethnic background. IL13 expression in human T cells is paralleled by extensive IL13 locus remodeling, which results in the appearance of multiple DNase I hypersensitive (HS) sites. Among these, HS4 in the distal IL13 promoter is constitutively present in both naive and polarized Th2 cells, and spans a single nucleotide polymorphism, IL13-1512AC (rs1881457), which is common and strongly associated with total serum IgE levels. This dissertation combines in vitro and ex vivo approaches to characterize the role of HS4 in the regulation of IL13 gene expression and to provide novel insights into the mechanisms that underlie the association between IL13-1512AC and allergic disease.
The results showed that HS4 acts as a novel cis-acting element that up-regulates IL13 transcription in activated Th2 cells. The enhancing activity of HS4 mapped within the 3' end of this element and was dependent on binding/recruitment of the transcription factors NF90 and NF45. Moreover, the IL13-1512C risk allele significantly enhanced HS4-dependent IL13 expression by creating a binding site for the transcription factor Oct-1. The increased expression of the -1512C allele was dependent on endogenous levels of Oct-1. Collectively, these results illustrate how a functional variant in an important regulatory element may modulate susceptibility to a common complex disease.
|Commitee:||Martinez, Fernando, Restifo, Linda, Wysocki, Vicki|
|School:||The University of Arizona|
|School Location:||United States -- Arizona|
|Source:||DAI-B 70/04, Dissertation Abstracts International|
|Subjects:||Molecular biology, Genetics, Immunology|
|Keywords:||Allergies, IL-13, Polymorphisms, T cells, Transcriptional regulation|
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