The Risk G Allele of the Single-Nucleotide Polymorphism rs928413 Creates a CREB1-Binding Site That Activates IL33 Promoter in Lung Epithelial Cells

• Published in: International journal of molecular sciences Vol. 19; no. 10; p. 2911
• Main Authors: Gorbacheva, Alisa M, Korneev, Kirill V, Kuprash, Dmitry V, Mitkin, Nikita A
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI 25.09.2018; MDPI AG
• Subjects: Alleles; asthma; Asthma - genetics; Asthma - metabolism; Cell Line, Tumor; Child; Communication; Cyclic AMP Response Element-Binding Protein - metabolism; Epithelial Cells - metabolism; Genetic Predisposition to Disease; Humans; inflammation; Interleukin-33 - genetics; Lung - cytology; Lung - metabolism; lung epithelium; MAP Kinase Signaling System; p38 MAPK pathway; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Protein Binding; Respiratory Mucosa - cytology; Respiratory Mucosa - metabolism; Transcriptional Activation; p38 MAPK pathway; asthma; lung epithelium; inflammation
• ISSN: 1422-0067; 1422-0067
• DOI: 10.3390/ijms19102911

Cytokine interleukin 33 (IL-33) is constitutively expressed by epithelial barrier cells, and promotes the development of humoral immune responses. Along with other proinflammatory mediators released by the epithelium of airways and lungs, it plays an important role in a number of respiratory pathologies. In particular, IL-33 significantly contributes to pathogenesis of allergy and asthma; genetic variations in the locus are associated with increased susceptibility to asthma. Large-scale genome-wide association studies have identified minor "G" allele of the single-nucleotide polymorphism rs928413, located in the promoter area, as a susceptible variant for early childhood and atopic asthma development. Here, we demonstrate that the rs928413(G) allele creates a binding site for the cAMP response element-binding protein 1 (CREB1) transcription factor. In a pulmonary epithelial cell line, activation of CREB1, presumably via the p38 mitogen-activated protein kinases (MAPK) cascade, activates the promoter containing the rs928413(G) allele specifically and in a CREB1-dependent manner. This mechanism may explain the negative effect of the rs928413 minor "G" allele on asthma development.