Dysregulation of TIM-3-galectin-9 pathway in the cystic fibrosis airways.

Hdl Handle:
http://hdl.handle.net/10147/126074
Title:
Dysregulation of TIM-3-galectin-9 pathway in the cystic fibrosis airways.
Authors:
Vega-Carrascal, Isabel; Reeves, Emer P; Niki, Toshiro; Arikawa, Tomohiro; McNally, Paul; O'Neill, Shane J; Hirashima, Mitsuomi; McElvaney, Noel G
Affiliation:
Respiratory Research Division, Department of Medicine, Education and Research Centre, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 9, Ireland.
Citation:
Dysregulation of TIM-3-galectin-9 pathway in the cystic fibrosis airways. 2011, 186 (5):2897-909 J. Immunol.
Journal:
Journal of immunology (Baltimore, Md. : 1950)
Issue Date:
1-Mar-2011
URI:
http://hdl.handle.net/10147/126074
DOI:
10.4049/jimmunol.1003187
PubMed ID:
21263071
Abstract:
The 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.
Item Type:
Article in Press
Language:
en
ISSN:
1550-6606

Full metadata record

DC FieldValue Language
dc.contributor.authorVega-Carrascal, Isabelen
dc.contributor.authorReeves, Emer Pen
dc.contributor.authorNiki, Toshiroen
dc.contributor.authorArikawa, Tomohiroen
dc.contributor.authorMcNally, Paulen
dc.contributor.authorO'Neill, Shane Jen
dc.contributor.authorHirashima, Mitsuomien
dc.contributor.authorMcElvaney, Noel Gen
dc.date.accessioned2011-03-29T13:47:00Z-
dc.date.available2011-03-29T13:47:00Z-
dc.date.issued2011-03-01-
dc.identifier.citationDysregulation of TIM-3-galectin-9 pathway in the cystic fibrosis airways. 2011, 186 (5):2897-909 J. Immunol.en
dc.identifier.issn1550-6606-
dc.identifier.pmid21263071-
dc.identifier.doi10.4049/jimmunol.1003187-
dc.identifier.urihttp://hdl.handle.net/10147/126074-
dc.description.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.-
dc.language.isoenen
dc.titleDysregulation of TIM-3-galectin-9 pathway in the cystic fibrosis airways.en
dc.typeArticle in Pressen
dc.contributor.departmentRespiratory Research Division, Department of Medicine, Education and Research Centre, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 9, Ireland.en
dc.identifier.journalJournal of immunology (Baltimore, Md. : 1950)en
dc.description.provinceLeinster-

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