Journal article
miR-31 Dysregulation in Cystic Fibrosis Airways Contributes to Increased Pulmonary Cathepsin S Production
American journal of respiratory and critical care medicine, Vol.190(2), pp.165-174
07/15/2014
DOI: 10.1164/rccm.201311-1986OC
PMCID: PMC4226050
PMID: 24940638
Abstract
Rationale:
Cathepsin S (CTSS) activity is increased in bronchoalveolar
lavage (BAL) fluid from patients with cystic fibrosis (CF). This activity contributes
to lung inflammation via degradation of antimicrobial proteins, such as lactoferrin
and members of the β-defensin family.
Objectives:
In this study, we investigated the hypothesis that airway
epithelial cells are a source of CTSS, and mechanisms underlying CTSS expression in
the CF lung.
Methods:
Protease activity was determined using fluorogenic activity
assays. Protein and mRNA expression were analyzed by ELISA, Western blotting, and
reverse-transcriptase polymerase chain reaction.
Measurements and Main Results:
In contrast to neutrophil elastase, CTSS
activity was detectable in 100% of CF BAL fluid samples from patients without
Pseudomonas aeruginosa
infection. In this study, we identified
epithelial cells as a source of pulmonary CTSS activity with the demonstration that
CF airway epithelial cells express and secrete significantly more CTSS than non-CF
control cells in the absence of proinflammatory stimulation. Furthermore, levels of
the transcription factor IRF-1 correlated with increased levels of its target gene
CTSS. We discovered that miR-31, which is decreased in the CF airways, regulates
IRF-1 in CF epithelial cells. Treating CF bronchial epithelial cells with a miR-31
mimic decreased IRF-1 protein levels with concomitant knockdown of CTSS expression
and secretion.
Conclusions:
The miR-31/IRF-1/CTSS pathway may play a functional role in
the pathogenesis of CF lung disease and may open up new avenues for exploration in
the search for an effective therapeutic target.
Details
- Title: Subtitle
- miR-31 Dysregulation in Cystic Fibrosis Airways Contributes to Increased Pulmonary Cathepsin S Production
- Creators
- Sinéad Weldon - Centre for Infection and Immunity, School of Medicine, Dentistry and Biomedical Sciences, andPaul McNally - Our Lady's Children's Hospital, Crumlin, Dublin, IrelandDanny F McAuley - Centre for Infection and Immunity, School of Medicine, Dentistry and Biomedical Sciences, andIrene K Oglesby - Respiratory Research Division, Department of Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland; andChristine L Wohlford-Lenane - Department of Paediatrics, University of Iowa, Iowa City, IowaJennifer A Bartlett - Department of Paediatrics, University of Iowa, Iowa City, IowaChristopher J Scott - School of Pharmacy, Queen's University Belfast, Belfast, Northern Ireland, United KingdomNoel G McElvaney - Respiratory Research Division, Department of Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland; andCatherine M Greene - Respiratory Research Division, Department of Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland; andPaul B McCray - Department of Paediatrics, University of Iowa, Iowa City, IowaClifford C Taggart - Centre for Infection and Immunity, School of Medicine, Dentistry and Biomedical Sciences, and
- Resource Type
- Journal article
- Publication Details
- American journal of respiratory and critical care medicine, Vol.190(2), pp.165-174
- DOI
- 10.1164/rccm.201311-1986OC
- PMID
- 24940638
- PMCID
- PMC4226050
- NLM abbreviation
- Am J Respir Crit Care Med
- ISSN
- 1073-449X
- eISSN
- 1535-4970
- Publisher
- American Thoracic Society
- Language
- English
- Date published
- 07/15/2014
- Academic Unit
- Microbiology and Immunology; Pulmonary Medicine; Stead Family Department of Pediatrics; Internal Medicine
- Record Identifier
- 9984093505502771
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