Type

Other / n/a

Authors

Catherine M Greene
Noel G McElvaney
Shane J O'neill
Robert Cummins
Patrick G Buckley
Tomás P Carroll
Tidi Hassan

Subjects

Biochemistry

Topics
western gene expression profiling alpha 1 antitrypsin deficiency polymerase chain reaction biomarkers pulmonary disease sequence analysis stress physiological stress humans cytokines adult micrornas female sequence analysis rna methylation physiological male asymptomatic diseases up regulation unfolded protein response chronic obstructive rna medicine and health sciences pulmonary disease chronic obstructive monocytes middle aged blotting gene silencing phenotype blotting western

miR-199a-5p silencing regulates the unfolded protein response in chronic obstructive pulmonary disease and α1-antitrypsin deficiency. (2014)

Abstract RATIONALE: Retention of abnormal α1-antitrypsin (AAT) activates the unfolded protein response in AAT-deficient monocytes. The regulatory role of microRNAs (miRNAs) in unfolded protein responses and chronic obstructive pulmonary disease pathogenesis has not been investigated.OBJECTIVES: To investigate miRNA expression and function in MM and ZZ monocytes and identify miRNA(s) regulating the unfolded protein response.METHODS: Peripheral blood monocytes were isolated from asymptomatic and symptomatic MM and ZZ individuals for miRNA expression profiling and pyrosequencing analysis. miRNA/gene and protein expression was measured with quantitative polymerase chain reaction and Western blotting. Overexpression and inhibition studies were performed with pre-miR or anti-miR, respectively. Luciferase reporter genes were used to elucidate direct miRNA-target interactions. Inflammatory cytokines were detected using the Meso Scale Discovery Plex assays.MEASUREMENTS AND MAIN RESULTS: Forty-three miRNAs were differentially expressed, with miR-199a-5p most highly up-regulated in asymptomatic ZZ versus MM monocytes. miR-199a-2 promoter hypermethylation inhibits miR-199a-5p expression and was increased in symptomatic MM and ZZ monocytes compared with asymptomatic counterparts. GRP78, activating transcription factor 6, p50, and p65 were increased in symptomatic versus asymptomatic ZZ monocytes. Reciprocal down- or up-regulation of these markers was observed after miRNA modulation. Direct miR-199a-5p targeting of activating transcription factor 6, p50, and p65 by miR-199a-5p was demonstrated using luciferase reporter systems. Overexpression of miR-199a-5p also decreased other arms of the UPR and expression of cytokines that are not putative targets.CONCLUSIONS: miR-199a-5p is a key regulator of the unfolded protein response in AAT-deficient monocytes, and epigenetic silencing of its expression regulates this process in chronic obstructive pulmonary disease.
Collections Ireland -> Royal College of Surgeons in Ireland -> Medicine Articles
Ireland -> Royal College of Surgeons in Ireland -> Department of Medicine

Full list of authors on original publication

Catherine M Greene, Noel G McElvaney, Shane J O'neill, Robert Cummins, Patrick G Buckley, Tomás P Carroll, Tidi Hassan

Experts in our system

1
Catherine M Greene
Royal College of Surgeons in Ireland
Total Publications: 150
 
2
Noel G McElvaney
Royal College of Surgeons in Ireland
Total Publications: 194
 
3
Shane J O'Neill
Royal College of Surgeons in Ireland
Total Publications: 84
 
4
Robert Cummins
Royal College of Surgeons in Ireland
Total Publications: 22
 
5
Tomás P Carroll
Royal College of Surgeons in Ireland
Total Publications: 26
 
6
Tidi Hassan
Royal College of Surgeons in Ireland