Human TH 2 cells respond to cysteinyl leukotrienes through selective expression of cysteinyl leukotriene receptor 1

Background Allergic asthma is characterized by reversible airway obstruction and bronchial hyperresponsiveness associated with TH 2 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 TH 2 responses in murine models, although the precise mechanisms are unresolved. Objectives Preliminary microarray studies suggested that human TH 2 cells might selectively express cysteinyl leukotriene receptor 1 (CYSLTR1) mRNA. We sought to establish whether human TH 2 cells are indeed a CysLT target cell type. Methods We examined the expression of CYSLTR1 using real-time PCR in human TH 1 and TH 2 cells. We functionally assessed cysteinyl leukotriene receptor 1 protein (CysLT1 ) expression using calcium flux, cyclic AMP, and chemotaxis assays. Results We show that human TH 2 cells selectively express CYSLTR1 mRNA at high levels compared with TH 1 cells after in vitro differentiation from naive precursors. Human TH 2 cells are selectively responsive to CysLTs in a calcium flux assay when compared with TH 1 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 TH 2 cells is mediated through CysLT1 coupled to Gα q and Gα i proteins, and both pathways can be completely inhibited by selective CysLT1 antagonists. LTD4 is also found to possess potent chemotactic activity for TH 2 cells at low nanomolar concentrations. Conclusions 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.