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

Hdl Handle:
http://hdl.handle.net/10147/207175
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:
J Immunol. 2011 Mar 1;186(5):2897-909. Epub 2011 Jan 24.
Journal:
Journal of immunology (Baltimore, Md. : 1950)
Issue Date:
1-Feb-2012
URI:
http://hdl.handle.net/10147/207175
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.
Language:
eng
MeSH:
Adult; Aged; Bronchi/immunology/metabolism/pathology; Bronchoalveolar Lavage Fluid/immunology; Cell Line, Transformed; Child; Cystic Fibrosis/*immunology/metabolism/*pathology; Cystic Fibrosis Transmembrane Conductance Regulator/antagonists &; inhibitors/physiology; Female; Galectins/biosynthesis/metabolism/*physiology; Humans; Ligands; Male; Membrane Proteins/biosynthesis/metabolism/*physiology; Middle Aged; Neutrophils/enzymology/immunology/pathology; Recombinant Proteins/pharmacology; Respiratory Mucosa/*immunology/metabolism/*pathology; Signal Transduction/*immunology; Up-Regulation/immunology; Young Adult
ISSN:
1550-6606 (Electronic); 0022-1767 (Linking)

Full metadata record

DC FieldValue Language
dc.contributor.authorVega-Carrascal, Isabelen_GB
dc.contributor.authorReeves, Emer Pen_GB
dc.contributor.authorNiki, Toshiroen_GB
dc.contributor.authorArikawa, Tomohiroen_GB
dc.contributor.authorMcNally, Paulen_GB
dc.contributor.authorO'Neill, Shane Jen_GB
dc.contributor.authorHirashima, Mitsuomien_GB
dc.contributor.authorMcElvaney, Noel Gen_GB
dc.date.accessioned2012-02-01T10:01:06Z-
dc.date.available2012-02-01T10:01:06Z-
dc.date.issued2012-02-01T10:01:06Z-
dc.identifier.citationJ Immunol. 2011 Mar 1;186(5):2897-909. Epub 2011 Jan 24.en_GB
dc.identifier.issn1550-6606 (Electronic)en_GB
dc.identifier.issn0022-1767 (Linking)en_GB
dc.identifier.pmid21263071en_GB
dc.identifier.doi10.4049/jimmunol.1003187en_GB
dc.identifier.urihttp://hdl.handle.net/10147/207175-
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.en_GB
dc.language.isoengen_GB
dc.subject.meshAdulten_GB
dc.subject.meshAgeden_GB
dc.subject.meshBronchi/immunology/metabolism/pathologyen_GB
dc.subject.meshBronchoalveolar Lavage Fluid/immunologyen_GB
dc.subject.meshCell Line, Transformeden_GB
dc.subject.meshChilden_GB
dc.subject.meshCystic Fibrosis/*immunology/metabolism/*pathologyen_GB
dc.subject.meshCystic Fibrosis Transmembrane Conductance Regulator/antagonists &en_GB
dc.subject.meshinhibitors/physiologyen_GB
dc.subject.meshFemaleen_GB
dc.subject.meshGalectins/biosynthesis/metabolism/*physiologyen_GB
dc.subject.meshHumansen_GB
dc.subject.meshLigandsen_GB
dc.subject.meshMaleen_GB
dc.subject.meshMembrane Proteins/biosynthesis/metabolism/*physiologyen_GB
dc.subject.meshMiddle Ageden_GB
dc.subject.meshNeutrophils/enzymology/immunology/pathologyen_GB
dc.subject.meshRecombinant Proteins/pharmacologyen_GB
dc.subject.meshRespiratory Mucosa/*immunology/metabolism/*pathologyen_GB
dc.subject.meshSignal Transduction/*immunologyen_GB
dc.subject.meshUp-Regulation/immunologyen_GB
dc.subject.meshYoung Adulten_GB
dc.titleDysregulation of TIM-3-galectin-9 pathway in the cystic fibrosis airways.en_GB
dc.contributor.departmentRespiratory Research Division, Department of Medicine, Education and Research, Centre, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin 9,, Ireland.en_GB
dc.identifier.journalJournal of immunology (Baltimore, Md. : 1950)en_GB
dc.description.provinceLeinster-

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