Human TH2 cells respond to cysteinyl leukotrienes through selective expression of cysteinyl leukotriene receptor 1

Allergic asthma is characterized by reversible airway obstruction and bronchial hyperresponsiveness associated with TH2 cell–mediated inflammation. Cysteinyl leukotrienes (CysLTs) are potent lipid mediators involved in bronchoconstriction, mucus secretion, and cell trafficking in asthmatic patients. Recent data have implicated CysLTs in the establishment and amplification of TH2 responses in murine models, although the precise mechanisms are unresolved. Preliminary microarray studies suggested that human TH2 cells might selectively express cysteinyl leukotriene receptor 1 (CYSLTR1) mRNA. We sought to establish whether human TH2 cells are indeed a CysLT target cell type. We examined the expression of CYSLTR1 using real-time PCR in human TH1 and TH2 cells. We functionally assessed cysteinyl leukotriene receptor 1 protein (CysLT1) expression using calcium flux, cyclic AMP, and chemotaxis assays. We show that human TH2 cells selectively express CYSLTR1 mRNA at high levels compared with TH1 cells after in vitro differentiation from naive precursors. Human TH2 cells are selectively responsive to CysLTs in a calcium flux assay when compared with TH1 cells with a rank order of potency similar to that described for CysLT1 (leukotriene [LT] D4 > LTC4 > LTE4). We also show that LTD4-induced signaling in TH2 cells is mediated through CysLT1 coupled to Gαq and Gαi proteins, and both pathways can be completely inhibited by selective CysLT1 antagonists. LTD4 is also found to possess potent chemotactic activity for TH2 cells at low nanomolar concentrations. These findings suggest a novel mechanism of action for CysLTs in the pathogenesis of asthma and provide a potential explanation for the anti-inflammatory effects of CysLT1 antagonists.