Dysregulation of TIM-3-galectin-9 pathway in the cystic fibrosis airways.
Reeves, Emer P
O'Neill, Shane J
McElvaney, Noel G
AffiliationRespiratory Research Division, Department of Medicine, Education and Research, Centre, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 9,, Ireland.
Bronchoalveolar Lavage Fluid/immunology
Cell Line, Transformed
Cystic Fibrosis Transmembrane Conductance Regulator/antagonists &
MetadataShow full item record
CitationJ Immunol. 2011 Mar 1;186(5):2897-909. Epub 2011 Jan 24.
JournalJournal of immunology (Baltimore, Md. : 1950)
AbstractThe T-cell Ig and mucin domain-containing molecules (TIMs) have emerged as promising therapeutic targets to correct abnormal immune function in several autoimmune and chronic inflammatory conditions. It has been reported that proinflammatory cytokine dysregulation and neutrophil-dominated inflammation are the main causes of morbidity in cystic fibrosis (CF). However, the role of TIM receptors in CF has not been investigated. In this study, we demonstrated that TIM-3 is constitutively overexpressed in the human CF airway, suggesting a link between CF transmembrane conductance regulator (CFTR) function and TIM-3 expression. Blockade of CFTR function with the CFTR inhibitor-172 induced an upregulation of TIM-3 and its ligand galectin-9 in normal bronchial epithelial cells. We also established that TIM-3 serves as a functional receptor in bronchial epithelial cells, and physiologically relevant concentrations of galectin-9 induced TIM-3 phosphorylation, resulting in increased IL-8 production. In addition, we have demonstrated that both TIM-3 and galectin-9 undergo rapid proteolytic degradation in the CF lung, primarily because of neutrophil elastase and proteinase-3 activity. Our results suggest a novel intrinsic defect that may contribute to the neutrophil-dominated immune response in the CF airways.
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- TLR-4-mediated innate immunity is reduced in cystic fibrosis airway cells.
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- Issue date: 2010 Apr
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- Issue date: 2013 Dec
- TLR-induced inflammation in cystic fibrosis and non-cystic fibrosis airway epithelial cells.
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- Issue date: 2005 Feb 1
- Anti-inflammatory effect of miglustat in bronchial epithelial cells.
- Authors: Dechecchi MC, Nicolis E, Norez C, Bezzerri V, Borgatti M, Mancini I, Rizzotti P, Ribeiro CM, Gambari R, Becq F, Cabrini G
- Issue date: 2008 Nov