Glucocorticoid Receptor Binding Inhibits an Intronic IL33 Enhancer and is Disrupted by rs4742170 (T) Allele Associated with Specific Wheezing Phenotype in Early Childhood

• Published in: International journal of molecular sciences Vol. 19; no. 12; p. 3956
• Main Authors: Gorbacheva, Alisa M, Kuprash, Dmitry V, Mitkin, Nikita A
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 09.12.2018; MDPI
• Subjects: Alleles; allergy; Anaphylaxis; Asthma; Binding sites; Children; Communication; Cortisol; Cytokines; Dermatitis; Epithelial cells; Epithelium; Genes; Genetic diversity; Genome-wide association studies; Genomes; Genotype & phenotype; Glucocorticoids; Hormones; Hypersensitivity; Immune response; Inflammation; lung epithelium; Mutation; Nucleotides; Pathogenesis; Phenotypes; Polymorphism; Proteins; Respiratory diseases; Risk; Single-nucleotide polymorphism; siRNA; Smooth muscle; Steroids; Transcription factors; Wheezing; allergy; asthma; glucocorticoids; lung epithelium; wheezing; inflammation
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms19123956

Interleukin 33 (IL-33) is a cytokine constitutively expressed by various cells of barrier tissues that contribute to the development of inflammatory immune responses. According to its function as an alarmin secreted by lung and airway epithelium, IL-33 plays a significant role in pathogenesis of allergic disorders. IL-33 is strongly involved in the pathogenesis of asthma, anaphylaxis, allergy and dermatitis, and genetic variations in locus are associated with increased susceptibility to asthma. Genome-wide association studies have identified risk "T" allele of the single-nucleotide polymorphism rs4742170 located in putative enhancer area as susceptible variant for development of specific wheezing phenotype in early childhood. Here, we demonstrate that risk "T" rs4742170 allele disrupts binding of glucocorticoid receptor (GR) transcription factor to putative enhancer. The promoter/enhancer constructs containing either 4742170 (T) allele or point mutations in the GR-binding site, were significantly more active and did not respond to cortisol in a pulmonary epithelial cell line. At the same time, the constructs containing rs4742170 (C) allele with a functional GR-binding site were less active and further inhibitable by cortisol. The latter effect was GR-dependent as it was completely abolished by GR-specific siRNA. This mechanism may explain the negative effect of the rs4742170 (T) risk allele on the development of wheezing phenotype that strongly correlates with allergic sensitization in childhood.