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

Abstract

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 IL33 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 IL33 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 IL33 putative enhancer. The IL33 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.

IL‐37 regulates allergic inflammation by counterbalancing pro‐inflammatory IL‐1 and IL‐33

“…Since our in vitro and in vivo experiments demonstrated that IL‐37 limits the pro‐inflammatory effects of IL‐1β and IL‐33 of cells in the pathogenesis of asthma (eg, MNCs and AECs), we hypothesized that patients with asthma exhibit an imbalance between anti‐inflammatory IL‐37 versus pro‐inflammatory IL‐1β and IL‐33. Since glucocorticoids directly and indirectly inhibit the expression and production of IL‐1β, 55‐57 IL‐33, 58‐60 and IL‐37, 61 we determined the mRNA expression and secreted protein levels of these cytokines in sputum cells of the lower airways and nasal secretions from healthy individuals and patients with allergic asthma (after glucocorticoid therapy had been discontinued) (Figure 6 and Suppl. Table ).…”

Association of IL33, IL1RL1, IL1RAP Polymorphisms and Asthma in Chinese Han Children

“…The glucocorticoid receptor (GR) is expressed in lung epithelial cells. GR is activated by glucocorticoids and transferred to the nucleus to regulate the expression level of genes involved in stress and steroid responses in inflammation, by binding to nuclear glucocorticoid response elements ( Surjit et al, 2011 ; Gorbacheva et al, 2018 ). The therapeutic effect of ICS is mainly to inhibit the expression of inflammatory genes through various DNA-binding mechanisms.…”

“…At present, the specific GR-DNA of GR target genes is unclear. The five prime ends, the first intron and the second intron regions of the IL33 gene have some typical characteristics of regulatory elements ( Gorbacheva et al, 2018 ).…”

“…Once the C allele at the rs4742170 site in lung cancer cells mutated to become a T allele, it was observed that the GR binding site was destroyed and the binding force between the GR and the IL33 gene was reduced ( Gorbacheva et al, 2018 ). The activity of the IL33 promoter was enhanced, resulting in increased expression of IL33.…”

Role of IL-1RL1/ST2 in infantile asthma

“…It contributes to the pathogenesis of in ammatory allergic diseases. Genetic variation of the IL-33 locus is strongly associated with increased susceptibility to allergic sensitization in childhood and the development of wheezing phenotypes [25]. A recent clinical report indicated that the interaction between IL-33 and CD4(+)CD25(+)Foxp3(+) regulatory T cells is implicated in the pathogenesis of asthma in children [26].…”