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J Allergy Clin Immunol. 2017 Mar;139(3):780-789. doi: 10.1016/j.jaci.2016.06.014. Epub 2016 Jul 2.

Transcriptional profiling identifies the long noncoding RNA plasmacytoma variant translocation (PVT1) as a novel regulator of the asthmatic phenotype in human airway smooth muscle.

Author information

1
Airways Disease, National Heart and Lung Institute, Imperial College, London & Royal Brompton NIHR Biomedical Research Unit, London, United Kingdom.
2
Respiratory Research Group, University Hospital of South Manchester, University of Manchester, Manchester, United Kingdom.
3
Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom.
4
Airways Disease, National Heart and Lung Institute, Imperial College, London & Royal Brompton NIHR Biomedical Research Unit, London, United Kingdom; Respiratory Research Group, University Hospital of South Manchester, University of Manchester, Manchester, United Kingdom; Department of Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom.
5
Dubowitz Neuromuscular Centre, Molecular Neurosciences Section, Developmental Neurosciences Programme, UCL Institute of Child Health, London, United Kingdom. Electronic address: mark.perry@ucl.ac.uk.

Abstract

BACKGROUND:

The mechanism underlying nonsevere and severe asthma remains unclear, although it is commonly associated with increased airway smooth muscle (ASM) mass. Long noncoding RNAs (lncRNAs) are known to be important in regulating healthy primary airway smooth muscle cells (ASMCs), whereas changed expression has been observed in CD8 T cells from patients with severe asthma.

METHODS:

Primary ASMCs were isolated from healthy subjects (n = 9) and patients classified as having nonsevere (n = 9) or severe (n = 9) asthma. ASMCs were exposed to dexamethasone and FCS. mRNA and lncRNA expression was measured by using a microarray and quantitative real-time PCR. Bioinformatic analysis was used to examine relevant biological pathways. Finally, the lncRNA plasmacytoma variant translocation 1 (PVT1) was inhibited by transfection of primary ASMCs with small interfering RNAs, and the effect on ASMC phenotype was examined.

RESULTS:

The mRNA expression profile was significantly different between patient groups after exposure to dexamethasone and FCS, and these were associated with biological pathways that might be relevant to the pathogenesis of asthma, including cellular proliferation and pathways associated with glucocorticoid activity. We also observed a significant change in lncRNA expression, yet the expression of only one lncRNA (PVT1) is decreased in patients with corticosteroid-sensitive nonsevere asthma and increased in patients with corticosteroid-insensitive severe asthma. Subsequent targeting studies demonstrated the importance of this lncRNA in controlling both proliferation and IL-6 release in ASMCs from patients with severe asthma.

CONCLUSIONS:

lncRNAs are associated with the aberrant phenotype observed in ASMCs from asthmatic patients. Targeting PVT1 might be effective in reducing airway remodeling in asthmatic patients.

KEYWORDS:

Asthma; IL-6; PVT1; airway smooth muscle; long noncoding RNA; proliferation; transcriptome

PMID:
27484035
PMCID:
PMC5338875
DOI:
10.1016/j.jaci.2016.06.014
[Indexed for MEDLINE]
Free PMC Article

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