Neutrophil-mediated IL-6 receptor trans-signaling and the risk of chronic obstructive pulmonary disease and asthma

Autor: Farahi, N, Paige, E, Balla, J, Prudence, E, Ferreira, RC, Southwood, M, Appleby, SL, Bakke, P, Gulsvik, A, Litonjua, AA, Sparrow, D, Silverman, EK, Cho, MH, Danesh, J, Paul, DS, Freitag, DF, Chilvers, ER
Přispěvatelé: Danesh, John [0000-0003-1158-6791], Paul, Dirk [0000-0002-8230-0116], Chilvers, Edwin [0000-0002-4230-9677], Apollo - University of Cambridge Repository
Jazyk: angličtina
Rok vydání: 2017
Předmět:
SOLUBLE RECEPTOR
Male
Biochemistry & Molecular Biology
ADAM PROTEASES
in vitro study
AIRWAY INFLAMMATION
Neutrophils
monocyte chemoattractant protein-1
chronic obstructive airway disease
lung
DOUBLE-BLIND
Pulmonary Disease
Chronic Obstructive
respiration disorders
tocilizumab
pulmonary artery
Humans
PRO-INFLAMMATORY ACTIVITIES
genes
interleukin 6 receptor
METAANALYSIS
Genetic Association Studies
squamous intraepithelial lesion
Genetics & Heredity
Science & Technology
interleukin-6
neutrophil
11 Medical And Health Sciences
06 Biological Sciences
asthma
Receptors
Interleukin-6
endothelial cells
respiratory tract diseases
RHEUMATOID-ARTHRITIS
LUNG-FUNCTION
homozygote
INTERLEUKIN-6 RECEPTOR
alleles
pmel17
biobanks
Female
LEUKOCYTE RECRUITMENT
Life Sciences & Biomedicine
signal transduction
extrinsic asthma
Popis: The Asp358Ala variant in the interleukin-6 receptor (IL-6R) gene has been implicated in asthma, autoimmune and cardiovascular disorders, but its role in other respiratory conditions such as chronic obstructive pulmonary disease (COPD) has not been investigated. The aims of this study were to evaluate whether there is an association between Asp358Ala and COPD or asthma risk, and to explore the role of the Asp358Ala variant in sIL-6R shedding from neutrophils and its pro-inflammatory effects in the lung. We undertook logistic regression using data from the UK Biobank and the ECLIPSE COPD cohort. Results were meta-analyzed with summary data from a further three COPD cohorts (7,519 total cases and 35,653 total controls), showing no association between Asp358Ala and COPD (OR = 1.02 [95% CI: 0.96, 1.07]). Data from the UK Biobank showed a positive association between the Asp358Ala variant and atopic asthma (OR = 1.07 [1.01, 1.13]). In a series of in vitro studies using blood samples from 37 participants, we found that shedding of sIL-6R from neutrophils was greater in carriers of the Asp358Ala minor allele than in non-carriers. Human pulmonary artery endothelial cells cultured with serum from homozygous carriers showed an increase in MCP-1 release in carriers of the minor allele, with the difference eliminated upon addition of tocilizumab. In conclusion, there is evidence that neutrophils may be an important source of sIL-6R in the lungs, and the Asp358Ala variant may have pro-inflammatory effects in lung cells. However, we were unable to identify evidence for an association between Asp358Ala and COPD.
Databáze: OpenAIRE
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