Leukotriene E(4) is a full functional agonist for human cysteinyl leukotriene type 1 receptor-dependent gene expression

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.