title: 15-Lipoxygenases regulate the production of chemokines in human lung macrophages.
abstract: OBJECTIVE
  15-Lipoxygenase (15-LOX) activity is associated with inflammation and immune regulation. The objectives of the present study were to investigate the expression of 15-LOX-1 and 15-LOX-2 and evaluate the enzymes' roles in the polarization of human lung macrophages (LMs) in response to LPS and Th2 cytokines (IL-4/-13).
  
  
  METHODS
  LMs were isolated from patients undergoing surgery for carcinoma. The cells were cultured with a 15-LOX inhibitor (PD146176 or ML351), a COX inhibitor (indomethacin), a 5-LOX inhibitor (MK886) or vehicle and then stimulated with LPS (10 ng · mL(-1)), IL-4 (10 ng · mL(-1)) or IL-13 (50 ng · mL(-1)) for 24 h. Levels of ALOX15 (15-LOX-1) and ALOX15B (15-LOX-2) transcripts were determined by real-time quantitative PCR. Immunoassays were used to measure levels of LPS-induced cytokines (TNF-α, CCL2, CCL3, CCL4, CXCL1, CXCL8 and CXCL10) and Th2 cytokine-induced chemokines (CCL13, CCL18 and CCL22) in the culture supernatant.
  
  
  RESULTS
  Stimulation of LMs with LPS was associated with increased expression of ALOX15B, whereas stimulation with IL-4/IL-13 induced the expression of ALOX15. PD146176 and ML351 (10 μM) reduced the release of the chemokines induced by LPS and Th2 cytokines. The effects of these 15-LOX inhibitors were maintained in the presence of indomethacin and MK886. Furthermore, indomethacin revealed the inhibitory effect of PD146176 on TNF-α release.
  
  
  CONCLUSIONS
  Inhibition of the 15-LOX pathways is involved in the down-regulation of the in vitro production of chemokines in LMs. Our results suggest that the 15-LOX pathways have a role in the pathogenesis of inflammatory lung disorders and may thus constitute a potential drug target.
authors.affiliation: Laboratoire de Pharmacologie UPRES EA220, Hôpital Foch, Suresnes, France.|UFR Sciences de la santé, Université Versailles Saint Quentin, Saint Quentin en Yvelines, France.
authors.forename: C
authors.initials: C
authors.lastname: Abrial
authors.affiliation: Laboratoire de Pharmacologie UPRES EA220, Hôpital Foch, Suresnes, France.|UFR Sciences de la santé, Université Versailles Saint Quentin, Saint Quentin en Yvelines, France.
authors.forename: S
authors.initials: S
authors.lastname: Grassin-Delyle
authors.affiliation: Laboratoire de Pharmacologie UPRES EA220, Hôpital Foch, Suresnes, France.|UFR Sciences de la santé, Université Versailles Saint Quentin, Saint Quentin en Yvelines, France.
authors.forename: H
authors.initials: H
authors.lastname: Salvator
authors.affiliation: Laboratoire de Pharmacologie UPRES EA220, Hôpital Foch, Suresnes, France.
authors.forename: M
authors.initials: M
authors.lastname: Brollo
authors.affiliation: Laboratoire de Pharmacologie UPRES EA220, Hôpital Foch, Suresnes, France.|UFR Sciences de la santé, Université Versailles Saint Quentin, Saint Quentin en Yvelines, France.
authors.forename: E
authors.initials: E
authors.lastname: Naline
authors.affiliation: Laboratoire de Pharmacologie UPRES EA220, Hôpital Foch, Suresnes, France.|UFR Sciences de la santé, Université Versailles Saint Quentin, Saint Quentin en Yvelines, France.
authors.forename: P
authors.initials: P
authors.lastname: Devillier
mesh_terms: D000368:Aged; D001093:Arachidonate 15-Lipoxygenase / Q000502:physiology*; D002478:Cells, Cultured; D018925:Chemokines / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008875:Middle Aged
chemical_list: D018925:Chemokines; D016859:Lipoxygenase Inhibitors; C515716:ALOX15 protein, human; C458528:ALOX15B protein, human; D001093:Arachidonate 15-Lipoxygenase