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Leukotriene E 4  (LTE 4 ) the most stable of the cysteinyl leukotrienes (cysLTs) binds poorly to classical type 1 (CysLT 1 ) and 2 (CysLT 2 ) 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 LTE 4 . To identify such a receptor two human mast cell lines, LAD2 and LUVA, were selected that differentially responded to LTE 4  when analysed by intracellular signalling and gene expression. Comparative transcriptome analysis and recombinant gene overexpression experiments revealed CysLT 1  as a receptor responsible for potent LTE 4 -induced response in LAD2 but not in LUVA cells, an observation confirmed further by gene knockdown and selective inhibitors. Lentiviral overexpression of CysLT 1  in LUVA cells augmented intracellular calcium signalling induced by LTE 4  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 CysLT 1 , and sustained intracellular calcium mobilisation and extracellular signal-regulated kinase (Erk) activation, are required for LTE 4 -mediated regulation of gene expression in human cells. Our study shows for the first time that CysLT 1  expression is critically important for responsiveness to LTE 4  within a human cell system.

Leukotriene E4 is a full functional agonist for human cysteinyl leukotriene type 1 receptor-dependent gene expression