title: Human T(H)2 cells respond to cysteinyl leukotrienes through selective expression of cysteinyl leukotriene receptor 1.
abstract: BACKGROUND
  Allergic asthma is characterized by reversible airway obstruction and bronchial hyperresponsiveness associated with T(H)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 T(H)2 responses in murine models, although the precise mechanisms are unresolved.
  
  
  OBJECTIVE
  Preliminary microarray studies suggested that human T(H)2 cells might selectively express cysteinyl leukotriene receptor 1 (CYSLTR1) mRNA. We sought to establish whether human T(H)2 cells are indeed a CysLT target cell type.
  
  
  METHODS
  We examined the expression of CYSLTR1 using real-time PCR in human T(H)1 and T(H)2 cells. We functionally assessed cysteinyl leukotriene receptor 1 protein (CysLT(1)) expression using calcium flux, cyclic AMP, and chemotaxis assays.
  
  
  RESULTS
  We show that human T(H)2 cells selectively express CYSLTR1 mRNA at high levels compared with T(H)1 cells after in vitro differentiation from naive precursors. Human T(H)2 cells are selectively responsive to CysLTs in a calcium flux assay when compared with T(H)1 cells with a rank order of potency similar to that described for CysLT(1) (leukotriene [LT] D(4) > LTC(4) > LTE(4)). We also show that LTD(4)-induced signaling in T(H)2 cells is mediated through CysLT(1) coupled to G(α)q and G(α)i proteins, and both pathways can be completely inhibited by selective CysLT(1) antagonists. LTD(4) is also found to possess potent chemotactic activity for T(H)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 CysLT(1) antagonists.
authors.affiliation: King's College London, London, UK.
authors.forename: Celine N
authors.initials: CN
authors.lastname: Parmentier
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Fuerst
authors.forename: Joanne
authors.initials: J
authors.lastname: McDonald
authors.forename: Holly
authors.initials: H
authors.lastname: Bowen
authors.forename: Tak H
authors.initials: TH
authors.lastname: Lee
authors.forename: James E
authors.initials: JE
authors.lastname: Pease
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Woszczek
authors.forename: David J
authors.initials: DJ
authors.lastname: Cousins
mesh_terms: D020013:Calcium Signaling / Q000276:immunology; D002633:Chemotaxis / Q000187:drug effects / Q000276:immunology; D003545:Cysteine / Q000378:metabolism / Q000494:pharmacology*; D044385:GTP-Binding Protein alpha Subunits / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D007155:Immunologic Factors / Q000378:metabolism / Q000494:pharmacology*; D017998:Leukotriene D4 / Q000494:pharmacology; D015289:Leukotrienes / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D018077:Receptors, Leukotriene / Q000235:genetics* / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism
chemical_list: D044385:GTP-Binding Protein alpha Subunits; D007155:Immunologic Factors; D015289:Leukotrienes; D018077:Receptors, Leukotriene; C112381:cysteinyl-leukotriene; D017998:Leukotriene D4; D003545:Cysteine; C083169:leukotriene D4 receptor