Abstract
Chronic mucus hyper-secretion (CMH) contributes to the morbidity and mortality of asthma and remains uncontrolled by current therapies in the subset of patients with severe, steroid resistant disease. Altered cross-talk between airway epithelium and airway smooth muscle cells (ASMCs), driven by pro-inflammatory cytokines such as IL-1β, provides a potential mechanism that influences CMH.
This study investigated mechanisms underlying CMH by comparing IL-1β-induced gene expression profiles between asthma and control-derived ASMCs and the subsequent paracrine influence on airway epithelial mucus production in-vitro.
IL-1β-treated ASMCs from asthmatic and healthy donors were profiled using microarray analysis and ELISA. Air-liquid interface (ALI)-cultured CALU-3 and primary airway epithelial cells were treated with identified candidates and mucus production assessed.
The IL-1β-induced CCL20 expression and protein release was increased in ASMCs from moderate compared to mild asthmatics and healthy controls. IL-1β induced lower MIR146A expression in asthma-derived ASMCs compared to controls. Decreased MIR146A expression was validated in-vivo in bronchial biopsies from 16 asthmatic versus 39 healthy donors. MiR-146a-5p overexpression abrogated CCL20 release in ASMCs. CCL20 treatment of ALI-cultured CALU-3 and primary airway epithelial cells induced mucus production, while CCL20 levels in sputum were associated with increased levels of CMH in asthmatic patients.
Elevated CCL20 production by ASMC, possibly resulting from dysregulated expression of the anti-inflammatory miR-146a-5p, may contribute to enhanced mucus production in asthma.
Footnotes
This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.
Conflict of interest: Alen Faiz
Conflict of interest: Dr. Weckmann has nothing to disclose.
Conflict of interest: Haitatip Tasena
Conflict of interest: Corneel J. Vermeulen
Conflict of interest: Maarten Van den Berge
Conflict of interest: Nick H.T. ten Hacken
Conflict of interest: Andrew J. Halayko
Conflict of interest: Jeremy P.T. Ward
Conflict of interest: Dr. Lee has nothing to disclose.
Conflict of interest: Gavin Tjin
Conflict of interest: Judith L. Black
Conflict of interest: Mehra Haghi
Conflict of interest: Dr. Xu has nothing to disclose.
Conflict of interest: Gregory G. King
Conflict of interest: Claude S. Farah
Conflict of interest: Brian G. Oliver
Conflict of interest: Irene H. Heijink
Conflict of interest: Janette K. Burgess
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