Please use this identifier to cite or link to this item: http://hdl.handle.net/2381/37263
Title: Leukotriene E4 is a full functional agonist for human cysteinyl leukotriene type 1 receptor-dependent gene expression
Authors: Foster, H. R.
Fuerst, E.
Branchett, W.
Lee, T. H.
Cousins, David John
Woszczek, G.
First Published: 2-Feb-2016
Publisher: Nature Publishing Group
Citation: Scientific Reports, 2016, 6, 20461
Abstract: Leukotriene E4 (LTE4) the most stable of the cysteinyl leukotrienes (cysLTs) binds poorly to classical type 1 (CysLT1) and 2 (CysLT2) receptors although it induces potent responses in human airways in vivo, such as bronchoconstriction, airway hyperresponsiveness and inflammatory cell influx suggesting the presence of a novel receptor that preferentially responds to LTE4. To identify such a receptor two human mast cell lines, LAD2 and LUVA, were selected that differentially responded to LTE4 when analysed by intracellular signalling and gene expression. Comparative transcriptome analysis and recombinant gene overexpression experiments revealed CysLT1 as a receptor responsible for potent LTE4-induced response in LAD2 but not in LUVA cells, an observation confirmed further by gene knockdown and selective inhibitors. Lentiviral overexpression of CysLT1 in LUVA cells augmented intracellular calcium signalling induced by LTE4 but did not restore full agonist responses at the gene expression level. Our data support a model where both an increased expression of Gαq-coupled CysLT1, and sustained intracellular calcium mobilisation and extracellular signal-regulated kinase (Erk) activation, are required for LTE4-mediated regulation of gene expression in human cells. Our study shows for the first time that CysLT1 expression is critically important for responsiveness to LTE4 within a human cell system.
DOI Link: 10.1038/srep20461
ISSN: 2045-2322
Links: http://www.nature.com/articles/srep20461
http://hdl.handle.net/2381/37263
Version: Publisher Version
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright © 2016, the authors. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
Appears in Collections:Published Articles, Dept. of Infection, Immunity and Inflammation

Files in This Item:
File Description SizeFormat 
Foster et al 2016.pdfPost-review (final submitted)2.02 MBAdobe PDFView/Open
srep20461.pdfPublished (publisher PDF)995.11 kBAdobe PDFView/Open


Items in LRA are protected by copyright, with all rights reserved, unless otherwise indicated.