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

Gorbacheva, Alisa M.; Korneev, Kirill V.; Kuprash, Dmitry V.; Mitkin, Nikita A.

doi:10.3390/ijms19102911

Open AccessCommunication

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

by

Alisa M. Gorbacheva

^1,2,

Kirill V. Korneev

^1,2

,

Dmitry V. Kuprash

^1,2 and

Nikita A. Mitkin

^1,*

¹

Laboratory of Intracellular Signaling in Health and Disease, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia

²

Biological Faculty, Lomonosov Moscow State University, Moscow 119234, Russia

^*

Author to whom correspondence should be addressed.

Int. J. Mol. Sci. 2018, 19(10), 2911; https://doi.org/10.3390/ijms19102911

Submission received: 4 September 2018 / Revised: 20 September 2018 / Accepted: 21 September 2018 / Published: 25 September 2018

(This article belongs to the Section Biochemistry)

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Abstract

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 IL33 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 IL33 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 IL33 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.

Keywords: asthma; lung epithelium; inflammation; p38 MAPK pathway

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MDPI and ACS Style

Gorbacheva, A.M.; Korneev, K.V.; Kuprash, D.V.; Mitkin, N.A. The Risk G Allele of the Single-Nucleotide Polymorphism rs928413 Creates a CREB1-Binding Site That Activates IL33 Promoter in Lung Epithelial Cells. Int. J. Mol. Sci. 2018, 19, 2911. https://doi.org/10.3390/ijms19102911

AMA Style

Gorbacheva AM, Korneev KV, Kuprash DV, Mitkin NA. The Risk G Allele of the Single-Nucleotide Polymorphism rs928413 Creates a CREB1-Binding Site That Activates IL33 Promoter in Lung Epithelial Cells. International Journal of Molecular Sciences. 2018; 19(10):2911. https://doi.org/10.3390/ijms19102911

Chicago/Turabian Style

Gorbacheva, Alisa M., Kirill V. Korneev, Dmitry V. Kuprash, and Nikita A. Mitkin. 2018. "The Risk G Allele of the Single-Nucleotide Polymorphism rs928413 Creates a CREB1-Binding Site That Activates IL33 Promoter in Lung Epithelial Cells" International Journal of Molecular Sciences 19, no. 10: 2911. https://doi.org/10.3390/ijms19102911

APA Style

Gorbacheva, A. M., Korneev, K. V., Kuprash, D. V., & Mitkin, N. A. (2018). The Risk G Allele of the Single-Nucleotide Polymorphism rs928413 Creates a CREB1-Binding Site That Activates IL33 Promoter in Lung Epithelial Cells. International Journal of Molecular Sciences, 19(10), 2911. https://doi.org/10.3390/ijms19102911

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

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