title: Leukotriene D4 and interleukin-13 cooperate to increase the release of eotaxin-3 by airway epithelial cells.
abstract: BACKGROUND
  Airway epithelial cells play a central role in the physiopathology of asthma. They release eotaxins when treated with T(H)2 cytokines such as interleukin (IL)-4 or IL-13, and these chemokines attract eosinophils and potentiate the biosynthesis of cysteinyl leukotrienes (cysLTs), which in turn induce bronchoconstriction and mucus secretion. These effects of cysLTs mainly mediated by CysLT(1) and CysLT(2) receptors on epithelial cell functions remain largely undefined. Because the release of inflammatory cytokines, eotaxins, and cysLTs occur relatively at the same time and location in the lung tissue, we hypothesized that they regulate inflammation cooperatively rather than redundantly. We therefore investigated whether cysLTs and the T(H)2 cytokines would act in concert to augment the release of eotaxins by airway epithelial cells.
  
  
  METHODS
  A549 cells or human primary bronchial epithelial cells were incubated with or without IL-4, IL-13, and/or LTD(4). The release of eotaxin-3 and the expression of cysLT receptors were assessed by ELISA, RT-PCR, and flow cytometry, respectively.
  
  
  RESULTS
  IL-4 and IL-13 induced the release of eotaxin-3 by airway epithelial cells. LTD(4) weakly induced the release of eotaxin-3 but clearly potentiated the IL-13-induced eotaxin-3 release. LTD(4) had no effect on IL-4-stimulated cells. Epithelial cells expressed CysLT(1) but not CysLT(2). CysLT(1) expression was increased by IL-13 but not by IL-4 and/or LTD(4). Importantly, the upregulation of CysLT(1) by IL-13 preceded eotaxin-3 release.
  
  
  CONCLUSIONS
  These results demonstrate a stepwise cooperation between IL-13 and LTD(4). IL-13 upregulates CysLT(1) expression and consequently the response to cysLTs This results in an increased release of eotaxin-3 by epithelial cells which at its turn increases the recruitment of leukocytes and their biosynthesis of cysLTs. This positive amplification loop involving epithelial cells and leukocytes could be implicated in the recruitment of eosinophils observed in asthmatics.
authors.affiliation: Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec, Université Laval, Québec, QC, Canada.
authors.forename: Véronique
authors.initials: V
authors.lastname: Provost
authors.forename: Anick
authors.initials: A
authors.lastname: Langlois
authors.forename: François
authors.initials: F
authors.lastname: Chouinard
authors.forename: Marek
authors.initials: M
authors.lastname: Rola-Pleszczynski
authors.forename: Jamila
authors.initials: J
authors.lastname: Chakir
authors.forename: Nicolas
authors.initials: N
authors.lastname: Flamand
authors.forename: Michel
authors.initials: M
authors.lastname: Laviolette
mesh_terms: D001249:Asthma / Q000378:metabolism*; D001980:Bronchi / Q000166:cytology / Q000378:metabolism*; D054423:Chemokine CCL24 / Q000096:biosynthesis; D000075906:Chemokine CCL26; D019742:Chemokines, CC / Q000096:biosynthesis*; D003545:Cysteine / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D004847:Epithelial Cells / Q000166:cytology; D005434:Flow Cytometry / Q000379:methods; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation; D018793:Interleukin-13 / Q000378:metabolism*; D015847:Interleukin-4 / Q000378:metabolism; D007700:Kinetics; D017998:Leukotriene D4 / Q000378:metabolism*; D015289:Leukotrienes / Q000378:metabolism*; D008954:Models, Biological; D011994:Recombinant Proteins / Q000378:metabolism; D018418:Th2 Cells / Q000166:cytology
chemical_list: C515484:CCL24 protein, human; C120429:CCL26 protein, human; D054423:Chemokine CCL24; D000075906:Chemokine CCL26; D019742:Chemokines, CC; D018793:Interleukin-13; D015289:Leukotrienes; D011994:Recombinant Proteins; C112381:cysteinyl-leukotriene; D015847:Interleukin-4; D017998:Leukotriene D4; D003545:Cysteine